Tricyclic inhibitors of poly(adp-ribose)polymerase

ABSTRACT

The invention provides for compositions comprising phosphorous containing tricyclic compounds, including phthalazin-1(2H)-one derivatives. The compounds are potent inhibitors of the enzyme poly(ADP-ribose)polymerase (PARP), particularly PARP-1 and potentially PARP-2. The also show good cellular activity in inhibiting poly(ADP-ribose) oligomer formation. The compounds may be useful as mono-therapy or in combination with other therapeutic agents in the treatment conditions where PARP is implicated, such as cancer, inflammatory diseases and ischemic conditions. Thus, also provided are methods for the treatment of a condition where PARP is implicated comprising administering to an effective amount of a compound of the invention to an individual in need thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/491,851 filed May 31, 2011, the disclosure of which isincorporated herein by reference in its entirety.

FIELD OF INVENTION

The present invention relates to phosphorous containing heterocycliccompounds, such as phthalazin-1(2H)-one derivatives, which areinhibitors of the enzyme poly(ADP-ribose)polymerase (PARP). Thecompounds may be useful as mono-therapy or in combination with othertherapeutic agents in the treatment conditions where PARP is implicated,such as cancer, inflammatory diseases and ischemic conditions.

BACKGROUND OF THE INVENTION

Poly(ADP-ribose) polymerases (PARP) constitute a family of eighteenproteins containing PARP catalytic domains (Amé et al. BioEssays (2004)26:882). These proteins include PARP-1, PARP-2, PARP-3, tankyrase-1,tankyrase-2, and others. The founding member, and also the most studiedPARP-1 is the most abundant protein in nucleus. PARP-1 consists of threemain domains: an amino (N)-terminal DNA-binding domain (DBD) containingtwo zinc fingers, the automodification domain, and a carboxy(C)-terminal catalytic domain.

PARP enzymes are nuclear and cytoplasmic enzymes that cleave NAD⁺ tonicotinamide and ADP-ribose to form long and branched ADP-ribosepolymers on target proteins, including topoisomerases, histones and PARPitself (Le Rhun et al, Biochem. Biophys. Res. Commun. (1998) 245:1-10).

Poly(ADP-ribosyl)ation has been implicated in several biologicalprocesses, including DNA repair, gene transcription, cell cycleprogression, cell apoptosis, cell necrosis, chromatin functions andgenomic stability. Thus PARP inhibitors may be useful in the treatment avariety of conditions where activities of PARP enzymes are implicated.

The vast majority of known PARP inhibitors interact with thenicotinamide binding domain of the enzyme and behave as competitiveinhibitors with respect to NAD⁺ (Ferraris, J. Med. Chem. (2010)53(12):4561-4584 and Bundschere et al, Anti-Cancer Agents in MedicinalChemistry (2009) 9:816-821). Structural analogues of nicotinamide, suchas benzamide and derivatives were among the first compounds to beinvestigated as PARP inhibitors.

Amide or aryl substituted 4-benzyl-2H-phthalazin-1-ones derivatives havebeen disclosed as inhibitors of PARP, e.g. in WO 2002/036576, WO2003/070707, WO 2003/093261, WO 2004/080976, WO 2007/045877, WO2007/138351. WO 2008/114023, WO 2008/122810, and WO 2009/093032. Certainamide substituted 6-benzylpyridazin-3(2H)-one derivatives were disclosedas potent inhibitors of PARP enzymes, e.g. in WO 2007/138351,US20080161280, US2008/0269234, WO2009/004356. WO2009/063244, and WO2009/034326.

However, many known PARP inhibitors suffer from either a weak inhibitoryactivity or lack of desirable pharmaceutical properties. Thus, thereremains a need for potent inhibitors of the PARP enzyme with appropriatepharmaceutical properties for clinical applications.

BRIEF SUMMARY OF THE INVENTION

Disclosed are methods and compositions for the treatment of a conditionwhere PARP is PARP is implicated, such as cancer, inflammatory diseasesand ischemic conditions.

In one aspect, provided is a compound of the formula (I):

wherein

-   -   each R^(A) and R^(B) is independently halo, substituted or        unsubstituted C₁-C₆ alkyl or R^(A) and R^(B) are taken together        with the carbon atoms to which they are attached to form a        substituted or unsubstituted 5, 6 or 7-membered ring containing        0, 1 or 2 heteroatoms selected from S, O and N;    -   each R¹ and R² is independently hydrogen, halo, hydroxy,        substituted or unsubstituted C₁-C₃ alkyl or substituted or        unsubstituted C₁-C₃ alkoxy;    -   Z is a 5 or 6-membered aryl or heteroaryl substituted with R^(C)        and R^(P);    -   R^(C) is hydrogen, halo, —CF₃, substituted or unsubstituted        C₁-C₃ alkyl or substituted or unsubstituted C₁-C₃ alkoxy;    -   R^(P) is a moiety of the formula (Ia) or (Ib):

-   -   each X is independently O, S or absent;    -   R^(D) is hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heterocyclyl, —SO₂R³, —C(O)R⁴,        —C(═N—CN)NR⁸R⁹ or —C(O)NR⁵R⁶;    -   R³ is a substituted or unsubstituted alkyl or substituted or        unsubstituted cycloalkyl;    -   R⁴ is a substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted alkoxy,        or substituted or unsubstituted heterocyclyl;    -   each R⁵ and R⁶ is independently hydrogen, substituted or        unsubstituted alkyl or substituted or unsubstituted cycloalkyl;    -   each R⁸ and R⁹ is independently hydrogen, substituted or        unsubstituted alkyl or substituted or unsubstituted cycloalkyl,        or R⁸ and R⁹ are taken together with the nitrogen atom to which        they are attached to form a heterocyclyl;    -   R^(E) is substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted aryl, or        —OR⁷; and    -   R⁷ is a substituted or unsubstituted alkyl or substituted or        unsubstituted cycloalkyl;        or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment, the PARP inhibitor compound includes any one, anycombination, or all of the compounds of Table 1; or a pharmaceuticallyacceptable salt or solvate thereof. In some embodiments, the compound iscapable of inhibiting PARP-1 enzymatic activity with an IC₅₀ of lessthan about 100 nM. In some embodiments, the compound has a PARP-1 enzymeinhibition IC₅₀ of less than about 1.000 nM, less than about 750 nM,less than about 500 nM, less than about 250 nM, less than about 150 nM,less than about 100 nM, less than about 50 nM, less than about 10 nM, orless than about 1 nM, as measured using the HT Universal ColorimetricPARP Assay Kit. In some embodiments, the compound is capable ofinhibiting intracellular poly(ADP-ribose) formation with an EC₅₀ of lessthan about 100 nM. In some embodiments, the compound is capable ofinhibiting intracellular poly(ADP-ribose) formation with an EC₅₀ of lessthan about 1,000 nM, less than about 750 nM, less than about 500 nM,less than about 250 nM, less than about 150 nM, less than about 100 nM,less than about 50 nM, less than about 10 nM, or less than about 1 nM inhuman cancer cells such as a human cervical carcinoma (e.g., C41 cells).

In another aspect, provided is any one of the PARP (e.g. PARP-1)inhibitor compounds present in a substantially pure form.

In another aspect, provided are formulations comprising any one of thecompounds described herein and a carrier (e.g., a pharmaceuticallyacceptable carrier). In some embodiments, the formulation is suitablefor administration to an individual. In some embodiments, theformulation comprises an effective amount of any one of the compoundsdescribed herein and a carrier (e.g., a pharmaceutically acceptablecarrier). In another aspect, provided are pharmaceutical formulationscomprising a PARP (e.g. PARP-1) inhibitor compound or a PARP (e.g.PARP-1) inhibitor compound in combination with a pharmaceuticallyacceptable carrier.

In another aspect, the invention provides method for the treatment orprevention of a condition which can be ameliorated by inhibition of PARP(e.g. PARP-1) in an individual in need thereof, the method comprisingadministering to the individual an effective amount of a compounddetailed herein, such as a compound of the formula (I), (II), (III),(IV), (V) or any variations thereof. In some embodiments, the conditionis cancer, such as a breast cancer, an ovarian cancer or a brain cancer,a cancer which is deficient in HR dependent DNA DSB repair activity, aBRCA-1 or BRCA-2 deficient tumor, or a PTEN mutant tumor. In someembodiments, the condition is an inflammatory disease or an autoimmunedisease. In some embodiments, the condition is ischemia, reperfusion orrenal failure. In some embodiments, the condition is a retroviralinfection.

Also provided is use of compounds detailed herein, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof, inthe manufacture of a medicament for the treatment or prevention of acondition which can be ameliorated by inhibition of PARP (e.g. PARP-1)in an individual in need thereof.

In another aspect, provided are kits for the treatment or prevention inan individual of a condition which can be ameliorated by inhibition ofPARP (e.g. PARP-1), comprising any one of the compounds detailed hereinor a pharmaceutically acceptable salt or solvate thereof; and packaging.In some embodiments, the kit comprises a formulation of any one of thecompounds described herein or a pharmaceutically acceptable salt orsolvate thereof; and packaging.

DETAILED DESCRIPTION OF THE INVENTION

The invention provides, inter alia, compositions comprising PARPinhibitors and methods for their use, including methods of treatingconditions where PARP is implicated such as cancer, inflammatorydiseases and ischemic conditions.

Definitions

Unless clearly indicated otherwise, the terms “a,” “an,” and the like,refer to one or more.

Reference to “about” a value or parameter herein includes (anddescribes) embodiments that are directed to that value or parameter perse. For example, description referring to “about X” includes descriptionof “X”.

It is also understood and clearly conveyed by this disclosure thatreference to “the compound” or “a compound” includes and refers to anycompounds or pharmaceutically acceptable salt or other form thereof asdescribed herein.

The abbreviations used herein have their conventional meaning within thechemical and biological arts, unless otherwise specified.

“Alkyl” as used herein by itself or as part of another substituent,refers to, unless otherwise stated, a saturated straight (i.e.,unbranched), branched or cyclic hydrocarbon chain, or combinationthereof. Particular alkyl groups are those having 1 to 20 carbon atoms(a “C₁-C₂₀ alkyl”). More particular alkyl groups are those having 1 to 8carbon atoms (a “C₁-C₈ alkyl”). When an alkyl residue having a specificnumber of carbons is named, any and all geometric isomers having thatnumber of carbons are intended to be encompassed and described; thus,for example, “butyl” is meant to include n-butyl, sec-butyl, isobutyl,tert-butyl and cyclobutyl; “propyl” includes n-propyl, isopropyl andcyclopropyl. When an alkyl residue having a specified range of carbonatoms is named, any and all alkyl groups having any specific number(s)of carbon atoms within the specified range, inclusive, are intended tobe encompassed and described; thus a “C₁-C₆ alkyl” includes an alkylgroup having 1, 2, 3, 4, 5 or 6 carbon atoms. Alkyl is exemplified bygroups such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl,iso-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl andcyclohexyl and the like. Cycloalkyl is a subset of alkyl and can consistof one ring, such as cyclohexyl, or multiple rings, such as adamantyl. Acycloalkyl comprising more than one ring may be fused, spiro or bridged,or combinations thereof. A preferred cycloalkyl is a saturated cyclichydrocarbon having from 3 to 13 annular carbon atoms. A more preferredcycloalkyl is a saturated cyclic hydrocarbon having from 3 to 8 annularcarbon atoms (a “C₃-C₈ cycloalkyl”). Examples of cycloalkyl groupsinclude adamantyl, decahydronaphthalenyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like.

“Aryl” or “Ar” as used herein by itself or as part of anothersubstituent, refers to, unless otherwise stated, an unsaturated aromaticcarbocyclic group having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl or anthryl) which condensed rings may ormay not be aromatic. In one variation, the aryl group contains from 6 to14 annular carbon atoms. An aryl group having more than one ring whereat least one ring is non-aromatic may be connected to the parentstructure at either an aromatic ring position or at a non-aromatic ringposition. In one variation, an aryl group having more than one ringwhere at least one ring is non-aromatic is connected to the parentstructure at an aromatic ring position. Examples of aryl groups include,but are not limited to, phenyl, 1-naphthyl, 2-naphthyl, and 4-biphenyl.

“Heteroaryl” or “HetAr” as used herein by itself or as part of anothersubstituent, refers to, unless otherwise stated, an unsaturated aromaticcyclic group having from 1 to 10 annular carbon atoms and at least oneannular heteroatom, including but not limited to heteroatoms such asnitrogen, oxygen and sulfur. A heteroaryl group may have a single ring(e.g., pyridyl, thiazolyl) or multiple condensed rings (e.g.,phthalazinyl, quinazolinyl) which condensed rings may or may not bearomatic. A heteroaryl group having more than one ring where at leastone ring is non-aromatic may be connected to the parent structure ateither an aromatic ring position or at a non-aromatic ring position. Inone variation, a heteroaryl group having more than one ring where atleast one ring is non-aromatic is connected to the parent structure atan aromatic ring position. Non-limiting examples of heteroaryl groupsare pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl,thiazolyl, thiadiazolyl, furyl, pyridyl, pyrimidyl, benzothiazolyl,purinyl, benzimidazolyl, indolyl, isoquinolyl, quinolyl, quinoxalinyl,quinazolinyl, quinolyl, phthalazinyl, and the like.

“Halo” or “halogen” as used herein by itself or as part of anothersubstituent, refers to, unless otherwise stated, a fluorine, chlorine,bromine, or iodine atom.

“Alkoxy” as used herein by itself or as part of another substituent,refers to, unless otherwise stated, the group alkyl-O—, which includes,by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy,tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, andthe like. “Substituted alkoxy” refers to the group substituted alkyl-O—.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” as used herein byitself or as part of another substituent, refers to, unless otherwisestated, a stable saturated or unsaturated non-aromatic group having asingle ring or multiple condensed rings, and having from 1 to 10 annularcarbon atoms and from 1 to 4 annular heteroatoms selected from the groupconsisting of O, N, P, Si and S, and wherein the nitrogen, phosphorusand sulfur atoms may optionally be oxidized and the nitrogen heteroatommay optionally be quaternized. A heterocycle comprising more than onering may be fused, spiro or bridged, or any combination thereof. Infused ring systems, one or more of the rings can be aryl or heteroaryl.A heterocycle having more than one ring where at least one ring isaromatic may be connected to the parent structure at either anon-aromatic ring position or at an aromatic ring position. In onevariation, a heterocycle having more than one ring where at least onering is aromatic is connected to the parent structure at a non-aromaticring position. Examples of heterocyclyl include, but are not limited to,1,2-dihydrophthalazin-1-yl, phthalazin-1(2H)-one-4-yl,1,4-azaphosphinanyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl,tetrahydrofuran-3-yl, pyrrolidin-1-yl, pyrrolidin-2-yl,tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1-piperazinyl,2-piperazinyl, I-azetidinyl, and the like.

The term “substituted” refers to the replacement of one or more hydrogenatoms of a moiety with a monovalent or divalent radical. “Optionallysubstituted” indicates that the moiety may be substituted orunsubstituted. A moiety lacking the terms “optionally substituted” and“substituted” is intended to be an unsubstituted moiety (e.g., “phenyl”is intended as an unsubstituted phenyl unless indicated as a substitutedphenyl or an optionally substituted phenyl). In some embodiments, an“optionally substituted” group is an unsubstituted group. In someembodiments, an “optionally substituted” group is a substituted group.For example, an “optionally substituted alkyl” in one embodiment is anunsubstituted alkyl and in another embodiment is a substituted alkyl.

Unless clearly indicated otherwise. “an individual” as used hereinintends a mammal, including but not limited to a human. The inventionmay find use in both human medicine and in the veterinary context.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a cytotoxic agent, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents. As used herein, the term“composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productwhich results, directly or indirectly, from combination of the specifiedingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The “pharmaceutically effective amount” or “therapeutically effectiveamount” will vary depending on the composition being administered, thecondition being treated/prevented, the severity of the condition beingtreated or prevented, the age and relative health of the individual, theroute and form of administration, the judgment of the attending medicalor veterinary practitioner, and other factors appreciated by the skilledartisan in view of the teaching provided herein.

The term “treatment” refers to the treatment of a mammal afflicted witha pathological condition and refers to an effect that alleviates thecondition, e.g., by killing the cancerous cells, but also to an effectthat results in the inhibition of the progress of the condition, andincludes a reduction in the rate of progress, a halt in the rate ofprogress, amelioration of the condition, and cure of the condition.

The term “prevention” includes providing prophylaxis with respect tooccurrence or recurrence of a disease in an individual. An individualmay be predisposed to, susceptible to the disease, or at risk ofdeveloping the disease, but has not yet been diagnosed with the disease.

The term “pharmaceutically acceptable” as used herein pertains tocompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of a subject (e.g. human) without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio. Each carrier,excipient, etc. must also be “acceptable” in the sense of beingcompatible with the other ingredients of the formulation.

A “pharmaceutically suitable carrier” or “pharmaceutically acceptablecarrier.” as used herein refers to pharmaceutical excipients, forexample, pharmaceutically, physiologically, acceptable organic, orinorganic carrier substances suitable for enteral or parenteralapplication which do not deleteriously react with the extract.

The term “adjunct” refers to the use of compounds in conjunction withknown therapeutic means. Such means include cytotoxic regimes of drugsand/or ionizing radiation as used in the treatment of different cancertypes. In particular, the active compounds are known to potentiate theactions of a number of cancer chemotherapy treatments, which include thetopoisomerase class of poisons (e. g. topotecan, irinotecan, rubitecan),most of the known alkylating agents (e. g. DTIC, temozolamide) andplatinum based drugs (e. g. carboplatin, cisplatin) used in treatingcancer.

PARP Inhibitors

In one aspect, provided is a compound of the formula (I):

wherein

-   -   each R^(A) and R^(B) is independently halo, substituted or        unsubstituted C₁-C₆ alkyl or R^(A) and R^(B) are taken together        with the carbon atoms to which they are attached to form a        substituted or unsubstituted 5, 6 or 7-membered ring containing        0, 1 or 2 heteroatoms selected from S, O and N;    -   each R¹ and R² is independently hydrogen, halo, hydroxy,        substituted or unsubstituted C₁-C₃ alkyl or substituted or        unsubstituted C₁-C₃ alkoxy;    -   Z is a 5 or 6-membered aryl or heteroaryl substituted with R^(C)        and R^(P);    -   R^(C) is hydrogen, halo, —CF₃, substituted or unsubstituted        C₁-C₃ alkyl or substituted or unsubstituted C₁-C₃ alkoxy;    -   R^(P) is a moiety of the formula (Ia) or (Ib):

-   -   each X is independently O, S or absent;    -   R^(D) is hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heterocyclyl, —SO₂R³, —C(O)R⁴,        —C(═N—CN)NR⁸R⁹ or —C(O)NR⁵R⁶;    -   R³ is a substituted or unsubstituted alkyl or substituted or        unsubstituted cycloalkyl;    -   R⁴ is a substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted alkoxy,        or substituted or unsubstituted heterocyclyl;    -   each R⁵ and R⁶ is independently hydrogen, substituted or        unsubstituted alkyl or substituted or unsubstituted cycloalkyl;    -   each R⁸ and R⁹ is independently hydrogen, substituted or        unsubstituted alkyl or substituted or unsubstituted cycloalkyl,        or R⁸ and R⁹ are taken together with the nitrogen atom to which        they are attached to form a heterocyclyl;    -   R^(E) is substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted aryl, or        —OR⁷; and    -   R⁷ is a substituted or unsubstituted alkyl or substituted or        unsubstituted cycloalkyl;        or a pharmaceutically acceptable salt or solvate thereof.

In one aspect, provided is a compound of the formula (I-1):

wherein

-   -   each R^(A) and R^(B) is independently halo, substituted or        unsubstituted C₁-C₆ alkyl or R^(A) and R^(B) are taken together        with the carbon atoms to which they are attached to form a        substituted or unsubstituted 5, 6 or 7-membered ring containing        0, 1 or 2 heteroatoms selected from S, O and N;    -   each R¹ and R² is independently hydrogen, halo, substituted or        unsubstituted C₁-C₃ alkyl or substituted or unsubstituted C₁-C₃        alkoxy;    -   Z is a 5 or 6-membered aryl or heteroaryl substituted with R^(C)        and R^(P);    -   R^(C) is hydrogen, halo, —CF₃, substituted or unsubstituted        C₁-C₃ alkyl or substituted or unsubstituted C₁-C₃ alkoxy;    -   R^(P) is a moiety of the formula (Ia) or (Ib):

-   -   each X is independently O, S or absent;    -   R^(D) is hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heterocyclyl, —SO₂R³, —C(O)R⁴,        —C(═N—CN)NR⁸R⁹ or —C(O)NR⁵R⁶;    -   R³ is a substituted or unsubstituted alkyl or substituted or        unsubstituted cycloalkyl;    -   R⁴ is a substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted alkoxy,        or substituted or unsubstituted heterocyclyl;    -   each R⁵ and R⁶ is independently hydrogen, substituted or        unsubstituted alkyl or substituted or unsubstituted cycloalkyl;    -   each R⁸ and R⁹ is independently hydrogen, substituted or        unsubstituted alkyl or substituted or unsubstituted cycloalkyl,        or R⁸ and R⁹ are taken together with the nitrogen atom to which        they are attached to form a heterocyclyl;    -   R^(E) is substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted aryl, or        —OR⁷; and    -   R⁷ is a substituted or unsubstituted alkyl or substituted or        unsubstituted cycloalkyl;        or a pharmaceutically acceptable salt or solvate thereof.

A “substituted” moiety, such as a substituted alkyl, substituted alkoxy,substituted aryl, substituted heteroaryl or substituted heterocyclyl,may have one or more substituents. The substituents on an substitutedmoiety of the formula (I) may be one, two, three, or more groupsselected from, but not limited to, hydroxyl, nitro, amino (e.g., —NH₂ ordialkyl amino), imino, cyano, halo (such as F, Cl, Br, I), haloalkyl(such as —CCl₃ or —CF₃), thio, sulfonyl, thioamido, amidino, imidino,oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido,carboxyl, formyl, alkyl, alkoxy, alkoxy-alkyl, alkylcarbonyl,alkylcarbonyloxy (—OCOR), aminocarbonyl, arylcarbonyl, aralkylcarbonyl,carbonylamino, heteroarylcarbonyl, heteroaralkyl-carbonyl, alkylthio,aminoalkyl, cyanoalkyl, carbamoyl (—NHCOOR— or —OCONHR—), urea(—NHCONHR—), aryl and the like, where R is any suitable group, e.g.,alkyl or alkylene. In some embodiments, the optionally substitutedmoiety is optionally substituted only with select radicals, as describedherein. In some embodiments, the above groups (e.g., alkyl groups) areoptionally substituted with, for example, alkyl (e.g., methyl or ethyl),haloalkyl (e.g., —CCl₃, —CH₂CHCl₂ or —CF₃), cycloalkyl (e.g., —C₃H₅,—C₄H₇, —C₅H₉), amino (e.g., —NH₂ or dialkyl amino), alkoxy (e.g.,methoxy), heterocyclyl (e.g., as morpholine, piperazine, piperidine,azetidine), hydroxyl, and/or heteroaryl (e.g., oxazolyl). In someembodiments, a substituent group is itself optionally substituted. Insome embodiments, a substituent group is not itself substituted. Thegroup substituted onto the substitution group can be, for example,carboxyl, halo, nitro, amino, cyano, hydroxyl, alkyl, alkenyl, alkynyl,alkoxy, aminocarbonyl, —SR, thioamido, —SO₃H, —SO₂R or cycloalkyl, whereR is any suitable group, e.g., a hydrogen or alkyl.

In some embodiments, each R¹ and R² is hydrogen. In some embodiments,one of R¹ and R² is hydrogen and the other is halo, substituted orunsubstituted C₁-C₃ alkyl or substituted or unsubstituted C₁-C₃ alkoxy.In some embodiments, each R¹ and R² is independently halo, substitutedor unsubstituted C₁-C₃ alkyl or substituted or unsubstituted C₁-C₃alkoxy. In some embodiments, each R¹ and R² is independently hydrogen orhalogen.

In some embodiments, each R¹ and R² is hydrogen, and one or both of R¹and R² are isotopically enriched with deuterium (²H). In one variationone of R¹ and R² is hydrogen and the other is deuterium. In anothervariation, both R¹ and R² are deuterium. In some embodiments, one of R¹and R² is hydroxy. In some embodiments, one of R¹ and R² is hydrogen andthe other is hydroxy.

It is understood and clearly conveyed herein that each and everyvariation of R¹ and R² described herein may be combined with each andevery variation of other variables (e.g., R^(A), R^(B), Z, R^(C) andR^(P)) described herein, where applicable, as if each and everycombination were listed separately.

In some embodiments, each R^(A) and R^(B) is independently halo orsubstituted or unsubstituted C₁-C₆ alkyl. In some embodiments, eachR^(A) and R^(B) is independently a halo group. In some embodiments, eachR^(A) and R^(B) is independently a substituted or unsubstituted C₁-C₆alkyl. In some embodiments, one of R^(A) and R^(B) is a halo group andthe other is a substituted or unsubstituted C₁-C₆ alkyl.

In some embodiments, R^(A) and R^(B) are taken together with the carbonatoms to which they are attached to form a substituted or unsubstituted5, 6 or 7-membered ring containing 0, 1 or 2 heteroatoms selected fromS, O and N. In some embodiments, R^(A) and R^(B) are taken together withthe carbon atoms to which they are attached to form a substituted orunsubstituted 5, 6 or 7-membered carbocycle. In some embodiments, R^(A)and R^(B) are taken together with the carbon atoms to which they areattached to form a substituted or unsubstituted 6-membered carbocycle.In some embodiments, R^(A) and R^(B) are taken together with the carbonatoms to which they are attached to form a substituted or unsubstituted5, 6 or 7-membered ring containing 1 or 2 heteroatoms selected from S, Oand N. In some embodiments, R^(A) and R^(B) are taken together with thecarbon atoms to which they are attached to form a substituted orunsubstituted 5, 6 or 7-membered ring containing one heteroatom selectedfrom S, O and N. In some embodiments, R^(A) and R^(B) are taken togetherwith the carbon atoms to which they are attached to form a substitutedor unsubstituted 6-membered aromatic ring (e.g., a phenyl ring). In someembodiments, R^(A) and R^(B) are taken together with the carbon atoms towhich they are attached to form a substituted or unsubstitutedheteroaromatic ring.

In some embodiments, the compound of formula (I) where R^(A) and R^(B)are together with the atoms to which they are attached to form anaromatic ring has the formula (II):

wherein R¹, R², R^(C), R^(P) and Z are as defined for the formula (I)and R^(F) is hydrogen, halo, —CF₃, substituted or unsubstituted C₁-C₃alkyl or substituted or unsubstituted C₁-C₃ alkoxy; or apharmaceutically acceptable salt or solvate thereof.

In some embodiments, R^(F) is hydrogen. In some embodiments, R^(F) ishalo (e.g., fluoro). In some embodiments, R^(F) is —CF₃, or substitutedor unsubstituted C₁-C₃ alkyl. In some embodiments, R^(F) is substitutedor unsubstituted C₁-C₃ alkoxy.

It is understood and clearly conveyed herein that each and everyvariation of R^(A) and R^(B) described herein may be combined with eachand every variation of other variables (e.g., R¹, R², Z, R^(C) andR^(P)) described herein, where applicable, as if each and everycombination were listed separately.

In some embodiments, at least one of R¹ and R² is hydrogen. In someembodiments, each R¹ and R² is hydrogen. In some embodiments, eachR^(F), R¹ and R² is hydrogen.

In some embodiments, Z is a 5 or 6-membered heteroaryl substituted withR^(C) and R^(P). In some embodiments, Z is a 5-membered heteroarylsubstituted with R^(C) and R^(P). In some embodiments, Z is a 6-memberedheteroaryl substituted with R^(C) and R^(P). In some embodiments, Z is a5 or 6-membered aryl substituted with R^(C) and R^(P). In someembodiments, Z is a 5-membered aryl substituted with R^(C) and R^(P). Insome embodiments, Z is a 6-membered aryl substituted with R^(C) andR^(P). In some embodiments, Z is a phenyl substituted with R^(C) andR^(P).

It is understood and clearly conveyed herein that each and everyvariation of Z described herein may be combined with each and everyvariation of other variables (e.g., R¹, R², R^(A), R^(B), R^(C) andR^(P)) described herein, where applicable, as if each and everycombination were listed separately.

In some embodiments, the compound is of the formula (II), where R¹, R²,R^(C), R^(F) and Z are as defined for the formula (II) and R^(P) is amoiety of the formula (Ia); the compound is of the formula (IIa). Insome embodiments, the compound is of the formula (II), where R¹, R²,R^(C), R^(F) and Z are as defined for the formula (II) and R^(P) is amoiety of the formula (Ib); the compound is of the formula (IIb).

The present invention also provides compounds of formula (III):

wherein R¹, R², R^(C), R^(P) and R^(F) are as defined for the formula(I) or (II); or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, at least one of R¹ and R² is hydrogen. In someembodiments, each R¹ and R² is hydrogen. In some embodiments, R^(F) ishydrogen. In some embodiments, R^(F) is halo (e.g., fluoro). In someembodiments, one or both R¹ and R² is isotopically enriched withdeuterium. In some embodiments, each R¹ and R² is deuterium.

In some embodiment, R^(C) is hydrogen. In some embodiments, R^(C) ishalo, —CF₃, substituted or unsubstituted C₁-C₃ alkyl or substituted orunsubstituted C₁-C₃ alkoxy. In some embodiments, R^(C) is a halo group(e.g., fluoro). In some embodiments, R^(C) is —CF₃. In some embodiments,R^(C) is substituted or unsubstituted C₁-C₃ alkyl. In some embodiments,R^(C) is substituted or unsubstituted C₁-C₃ alkoxy. In some embodiments,R^(C) is connected to the phenyl ring at a position ortho to the R^(P)group. In some embodiments, R^(C) is connected to the phenyl ring at aposition para to the R^(P) group. In some embodiments, R^(C) isconnected to the phenyl ring at a position meta to the R^(P) group.

In some embodiments, R^(P) is of the formula (Ia) where X is absent. Insome embodiments, R^(P) is of the formula (Ia) where X is O. In someembodiments, R^(P) is of the formula (Ia) where X is S.

In some embodiments, R^(P) is of the formula (Ib) where X is absent. Insome embodiments, R^(P) is of the formula (Ib) where X is O. In someembodiments, R^(P) is of the formula (Ib) where X is S.

In some preferred embodiments, the compound is of the formula (IIa):

wherein R^(C), R^(D) and R^(F) are as defined for the formula (I), (II)or (III); or a pharmaceutically acceptable salt or solvate thereof.

In one variation, R^(D) is hydrogen, substituted or unsubstituted alkyl,or substituted or unsubstituted cycloalkyl. In another variation, R^(D)is substituted or unsubstituted C₁-C₆ alkyl. In some embodiments. R^(D)is an unsubstituted C₁-C₆ alkyl. In another variation, R^(D) is asubstituted or unsubstituted C₁-C₆ cycloalkyl. In another variation,R^(D) is selected from the group consisting of hydrogen, methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, isopentyl,trifluoroethyl, cyclopropylmethyl, cyclopropyl, cyclobutyl andcyclopentyl. In another variation, R^(D) is hydrogen, methyl or ethyl.

In some embodiments, R^(D) is methyl or ethyl. In another variation,R^(D) is a substituted or unsubstituted aryl. In another variation,R^(D) is substituted or unsubstituted phenyl. In another variation,R^(D) is substituted or unsubstituted heteroaryl. In another variation,R^(D) is a substituted or unsubstituted 6-membered heteroaryl. Inanother variation, R^(D) is a substituted or unsubstituted 5-memberedheteroaryl. In another variation, R^(D) is a substituted orunsubstituted heteroaryl selected from the group consisting ofpyridinyl, pyridazinyl, pyrimidinyl, quinazolinyl, imidazolyl, oxazolyl,oxadiazolyl, pyrazolyl, thiazolyl, and thiadiazolyl. In anothervariation, R^(D) is a substituted or unsubstituted heteroaryl selectedfrom the group consisting of pyridinyl, pyridazinyl, pyrimidinyl,quinazolinyl, thiazolyl, and thiadiazolyl. In another variation, R^(D)is a substituted or unsubstituted pyridinyl (e.g., 2-pyridyl,3-pyridinyl or 4-pyridyl). In another variation, R^(D) is a substitutedor unsubstituted pyrimidinyl (e.g., 2-pyrimidyl, 4-pyrimidinyl or5-pyrimidyl). In another variation, R^(D) is substituted orunsubstituted heterocyclyl.

In one variation, R^(D) is —C(O)NR⁵R⁶, where each R⁵ and R⁶ isindependently hydrogen, substituted or unsubstituted alkyl orsubstituted or unsubstituted cycloalkyl. In another variation, each R⁵and R⁶ is independently hydrogen or an unsubstituted alkyl. In oneparticular variation, each R⁵ and R⁶ is methyl.

In one variation, R^(D) is —SO₂R³ where R³ is a substituted orunsubstituted alkyl or substituted or unsubstituted cycloalkyl. Inanother variation, R³ is a substituted or unsubstituted cycloalkyl(e.g., cyclopropyl). In another variation, R³ is a substituted orunsubstituted alkyl (e.g., methyl).

In some embodiments, R^(D) is —C(O)R⁴ where R⁴ is a substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted alkoxy, or substituted or unsubstitutedheterocyclyl. In another variation, R⁴ is a substituted or unsubstitutedalkyl or substituted or unsubstituted cycloalkyl. In another variation,R⁴ is an unsubstituted C₁-C₆ alkyl or unsubstituted C₁-C₆ cycloalkyl. Inanother variation, R⁴ is a substituted or unsubstituted heterocyclyl. Inanother variation, R⁴ is a substituted or unsubstituted heterocyclylselected from pyrrolidinyl and tetrahydrofuranyl.

In some embodiments, R^(D) is —C(═N—CN)NR⁸R⁹ where each R⁸ and R⁹ isindependently hydrogen, substituted or unsubstituted alkyl orsubstituted or unsubstituted cycloalkyl. In some embodiments, R^(D) is—C(═N—CN)NR⁸R⁹ where R⁸ and R⁹ are taken together with the nitrogen atomto which they are attached to form a substituted or unsubstitutedheterocyclyl. In another variation, R^(D) is —C(═N—CN)NR⁸R⁹ where R⁸ andR⁹ ae taken together with the nitrogen atom to which they are attachedto form 1-azetidinyl.

In some embodiments, R^(D) is selected from the group consisting of:

In some preferred embodiments, the compound is of the formula (IIb):

wherein R^(C), R^(E) and R^(F) are as defined for the formula (I), (II)or (III); or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, R^(E) is substituted or unsubstituted alkyl, orsubstituted or unsubstituted cycloalkyl. In another variation, R^(E) isa substituted or unsubstituted alkyl. In another variation, R^(E) is anunsubstituted alkyl. In another variation, R^(E) is an unsubstitutedC₁-C₆ alkyl. In another variation, R^(E) is methyl, ethyl or isopropyl.In another variation, R^(E) is substituted or unsubstituted aryl.

In some embodiments, R^(E) is —OR⁷ where R⁷ is a substituted orunsubstituted alkyl or substituted or unsubstituted cycloalkyl. In onevariation, R⁷ is a substituted or unsubstituted C₁-C₆ alkyl orsubstituted or unsubstituted C₁-C₆ cycloalkyl. In another variation, R⁷is an unsubstituted C₁-C₆ alkyl (e.g., methyl or ethyl).

The embodiments and variations described herein are suitable forcompounds of any formulae detailed herein, where applicable.

In referring to “variations” of formula (I), (II), (III), and/or (IV),unless clearly dictated otherwise by context or inconsistent withchemical rationale, it is intended that variations refer, for example,to various sub-formulae of formula (II), (III), and/or (IV), forexample, formula (IIa), (IIb), (IIIa), (IIIb), (IVa), (IVb), etc. as setforth herein.

In some preferred embodiments, the compound is of the formula (IV):

wherein

-   -   R^(C) is hydrogen, halo, —CF₃, substituted or unsubstituted        C₁-C₃ alkyl or substituted or unsubstituted C₁-C₃ alkoxy;    -   R^(P) is a moiety of the formula (Ia) or (Ib):

-   -   X is O;    -   R^(D) is hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl,        substituted or unsubstituted heterocyclyl, —SO₂R³, —C(O)R⁴,        —C(═N—CN)NR⁸R⁹ or —C(O)NR⁵R⁶;    -   R³ is a substituted or unsubstituted alkyl or substituted or        unsubstituted cycloalkyl;    -   R⁴ is a substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted alkoxy,        or substituted or unsubstituted heterocyclyl;    -   each R⁵ and R⁶ is independently hydrogen, substituted or        unsubstituted alkyl or substituted or unsubstituted cycloalkyl;    -   each R⁸ and R⁹ is independently hydrogen, substituted or        unsubstituted alkyl or substituted or unsubstituted cycloalkyl,        or R⁸ and R⁹ are taken together with the nitrogen atom to which        they are attached to form a heterocyclyl;    -   R^(E) is substituted or unsubstituted alkyl, substituted or        unsubstituted cycloalkyl, substituted or unsubstituted aryl, or        —OR⁷; and    -   R⁷ is a substituted or unsubstituted alkyl or substituted or        unsubstituted cycloalkyl;        or a pharmaceutically acceptable salt or solvate thereof.

In some preferred embodiments, the compound is of the formula (IVa):

wherein R^(C) and R^(D) are as defined for the formula (IV); or apharmaceutically acceptable salt or solvate thereof.

In some variations, the compound is of the formula (IVa) where R^(D) isas defined for variations of the formula (IIIa), where applicable, as ifeach and every variation is individually recited for the formula (IVa).

In one variation, the compound is of the formula (IVa) where R^(D) ishydrogen, substituted or unsubstituted alkyl, or substituted orunsubstituted cycloalkyl, or a pharmaceutically acceptable salt orsolvate thereof. In another variation, R^(D) is selected from the groupconsisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, t-butyl, isopentyl, trifluoroethyl, cyclopropylmethyl,cyclopropyl, cyclobutyl and cyclopentyl. In another variation, R^(D) isa substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl. In a particular variation, R^(D) is substituted orunsubstituted phenyl. In one variation, R^(D) is a substituted orunsubstituted heteroaryl selected from the group consisting ofpyridinyl, pyridazinyl, pyrimidinyl, quinazolinyl, imidazolyl, oxazolyl,oxadiazolyl, pyrazolyl, thiazolyl, and thiadiazolyl. In anothervariation, R^(D) is —C(O)NR⁵R⁶, —SO₂R³, or —C(═N—CN)NR⁸R⁹. In anothervariation, R^(D) is —C(O)NR⁵R⁶ where each R⁵ and R⁶ is methyl. Inanother variation, R^(D) is —C(═N—CN)NR⁸R⁹ where each R⁸ and R⁹ isindependently hydrogen, substituted or unsubstituted alkyl orsubstituted or unsubstituted cycloalkyl. In another variation, R^(D) is—C(═N—CN)NR⁸R⁹ where R⁸ and R⁹ are taken together with the nitrogen atomto which they are attached to form a heterocyclyl (e.g., 1-azetidinyl).In another variation, R^(D) is —C(O)R⁴. In some of these variations, R⁴is an unsubstituted C₁-C₆ alkyl or unsubstituted C₁-C₆ cycloalkyl. Insome of these variations, R⁴ is a substituted or unsubstitutedheterocyclyl selected from pyrrolidinyl and tetrahydrofuranyl.

In one variation, provided is a compound of the formula (IVa), whereR^(C) is halo (e.g., fluoro) and R^(D) is as defined for the formula(IV). In some of these variations, R^(D) is selected from the groupconsisting of:

In some preferred embodiments, the compound is of the formula (IVb):

wherein R^(C) and R^(E) are as defined for the formula (IV); or apharmaceutically acceptable salt or solvate thereof.

In one variation, the compound is of the formula (IVb) where R^(E) issubstituted or unsubstituted alkyl, substituted or unsubstitutedcycloalkyl or —OR⁷; or a pharmaceutically acceptable salt or solvatethereof. In some of these variations, R^(E) is an unsubstituted C₁-C₆alkyl. In some of these variations, R^(E) is —OR⁷ where R⁷ is anunsubstituted C₁-C₆ alkyl.

In another variation, the compound is of the formula (IVb) where R^(C)is halo (e.g., fluoro) and R^(E) is substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl or —OR⁷; or a pharmaceuticallyacceptable salt or solvate thereof. In some of these variations, R^(E)is an unsubstituted C₁-C₆ alkyl (e.g., methyl, ethyl or isopropyl). Insome of these variations, R^(E) is —OR⁷ where R⁷ is an unsubstitutedC₁-C₆ alkyl (e.g., ethyl).

In some embodiments, the compound is of the formula (V):

wherein

-   -   each R¹ and R² is independently hydrogen, halo, hydroxy,        substituted or unsubstituted C₁-C₃ alkyl or substituted or        unsubstituted C₁-C₃ alkoxy;    -   R^(D) is hydrogen, substituted or unsubstituted alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted aryl, substituted or unsubstituted heteroaryl, or        substituted or unsubstituted heterocyclyl; and    -   R^(F) is hydrogen, halo, —CF₃, substituted or unsubstituted        C₁-C₃ alkyl or substituted or unsubstituted C₁-C₃ alkoxy;        or a pharmaceutically acceptable salt or solvate thereof.

In some embodiments, R^(F) is hydrogen. In some embodiments, R^(F) ishalo (e.g., fluoro). In some embodiments, R^(D) is hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted cycloalkyl, orsubstituted or unsubstituted heteroaryl. In some embodiments, R^(D) ishydrogen. In some embodiments, R^(D) is substituted alkyl (e.g.,benzyl). In some embodiments, R^(D) is substituted or unsubstitutedcycloalkyl (e.g., cyclopropyl). In some embodiments, R^(D) issubstituted or unsubstituted heteroaryl (e.g., 2-pyrimidinyl). In someembodiments, each R¹ and R² is independently hydrogen or hydroxy. Insome embodiments, each R¹ and R² is hydrogen. In some embodiments, eachR¹ and R² is hydrogen, and one or both of R¹ and R² are isotopicallyenriched with deuterium (²H). In one variation one of R¹ and R² ishydrogen and the other is deuterium. In another variation, both R¹ andR² are deuterium. In some embodiments, one of R¹ and R² is hydroxy. Insome embodiments, one of R¹ and R² is hydrogen and the other is hydroxy.

The compounds depicted herein may be present as salts even if salts arenot depicted and it is understood that the invention embraces all saltsand solvates (e.g., hydrate) of the compounds depicted here, as well asthe non-salt and non-solvate form of the compound, as is well understoodby the skilled artisan. In some embodiments, the salts of the compoundsof the invention are pharmaceutically acceptable salts.

It should be understood that a reference to a pharmaceuticallyacceptable salt includes the solvent addition forms or crystal formsthereof, particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and are oftenformed during the process of crystallization. Hydrates are formed whenthe solvent is water, or alcoholates are formed when the solvent isalcohol. Polymorphs include the different crystal packing arrangementsof the same elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature may cause asingle crystal form to dominate.

Where one or more tertiary amine moiety is present in the compound, suchas the compound of the formula (I), (II), (III) or (IV), the N-oxidesare also provided and described. The N-oxides may be formed byconventional means, such as reacting the compound of formula (I) withoxone in the presence of wet alumina.

The compounds depicted herein may have asymmetric centers, chiral axis,and/or chiral planes (as described in: E. L. Eliel and S. H. Wilen,Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994,pages 1119-1190), and occur as racemates, racemic mixtures where oneenantiomer may be enriched, individual diastereomers, and mixtures ofstereoisomers. All stereoisomers, including enantiomers anddiastereomers are embraced by the present invention.

The compounds depicted herein may exist as tautomers. Both tautomericforms are intended to be encompassed by the scope of the invention, eventhough only one tautomeric structure may be depicted.

The compounds herein may also contain unnatural proportions of atomicisotopes at one or more of the atoms that constitute such compounds. Insome embodiments, the compound is isotopically-labeled, such as anisotopically-labeled compound of the formula (I), (II), (III) or (IV),where a fraction of one or more atoms are replaced by an isotope of thesame element. Exemplary isotopes that can be incorporated into compoundsof the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorus, sulfur, chlorine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵O,¹⁷O, ³²P, ³⁵S, ¹⁸F, ³⁶Cl. Certain isotope labeled compounds (e.g. ³H and¹⁴C) are useful in compound or substrate tissue distribution study.Wherein certain heavier isotope (e.g. ²H) may afford certaintherapeutical advantage resulting from possible greater metabolicstability.

The present invention includes within its scope prodrugs of thecompound, such as the compound of the formula (I), (II), (III) or (IV).In general, such prodrugs are functional derivatives of the compound,such as functional derivatives of the compound of the formula (I), (II),(III) or (IV), which are readily convertible in vivo into the requiredcompound of the formula (I), (II), (III) or (IV). Conventionalprocedures for the selection and preparation of suitable prodrugderivatives are described, for example, in “Prodrugs: Challenges andRewards”, ed. V. J. Stella et al, Springer, 2007. A prodrug may be apharmacologically inactive derivative of a biologically active substance(the “parent drug” or “parent molecule”) that requires transformationwithin the body in order to release the active drug, and that hasimproved delivery properties over the parent drug molecule. Thetransformation in vivo may be, for example, as the result of somemetabolic process, such as chemical or enzymatic hydrolysis of acarboxylic, phosphoric or sulfuric ester, or reduction or oxidation of asusceptible functionality.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form. Unlessotherwise stated, “substantially pure” intends a composition thatcontains no more than 30% impurity, wherein the impurity denotes acompound other than the compound comprising the majority of thecomposition or a salt thereof. In some embodiments, a composition ofsubstantially pure compound or a salt thereof is provided wherein thecomposition contains no more than about 30%, about 25%, about 20%, about15%, about 10%, about 5%, about 3% or about 1% impurity.

In one aspect, provided are kits comprising a compound of the invention,or a salt or solvate thereof, and suitable packaging. In one embodiment,a kit further comprises instructions for use. In one aspect, a kitcomprises a compound of the invention, or a salt or solvate thereof, andinstructions for use of the compounds in the treatment or prevention ofa condition which can be ameliorated by inhibition of PARP (e.g. PARP-1)in an individual in need thereof.

Articles of manufacture comprising a compound of the invention, or asalt or solvate thereof, in a suitable container are provided. Thecontainer may be a vial, jar, ampoule and the like.

Representative examples of compounds detailed herein, includingintermediates and final compounds according to the invention aredepicted in the Tables and Examples below. It is understood that in oneaspect, any of the compounds may be used in the methods detailed herein,including, where applicable, intermediate compounds that may be isolatedand administered to an individual.

Representative compounds of the invention are shown in Table 1. In someembodiments, the invention provides a compound of Table 1, in its freebase form or as pharmaceutically acceptable salts, or a stereoisomer ora tautomer thereof.

TABLE 1 Exemplary compounds Compound Example No.4-(3-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-4- 1fluorobenzyl)phthalazin-1(2H)-one4-(3-(1-(cyclopentanecarbonyl)-4-oxido-1,4-azaphosphinan-4-yl)-4- 2fluorobenzyl)phthalazin-1(2H)-one4-(3-(1-(cyclopropanecarbonyl)-4-oxido-1,4-azaphosphinan-4-yl)-4- 3fluorobenzyl)phthalazin-1(2H)-one4-(3-(1-(cyclobutanecarbonyl)-4-oxido-1,4-azaphosphinan-4-yl)-4- 4fluorobenzyl)phthalazin-1(2H)-one4-(3-(1-(3,3-dimethylbutanoyl)-4-oxido-1,4-azaphosphinan-4-yl)-4- 5fluorobenzyl)phthalazin-1(2H)-one4-(3-(1-(3,3-difluoropyrrolidine-1-carbonyl)-4-oxido-1,4-azaphosphinan-6 4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(tetrahydrofuran-2-carbonyl)-1,4- 7azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-pivaloyl-1,4-azaphosphinan-4- 8yl)benzyl)phthalazin-1(2H)-one4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-N,N- 9dimethyl-1,4-azaphosphinane-1-carboxamide 4-oxide4-(4-fluoro-3-(4-oxido-1-pivaloyl-1,4-azaphosphinan-4- 10yl)benzyl)phthalazin-1(2H)-one(E/Z)-N-(azetidin-1-yl(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1- 11yl)methyl)phenyl)-4-oxido-1,4-azaphosphinan-1-yl)methylene)cyanamide4-(4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4- 12yl)benzyl)phthalazin-1(2H)-one4-(3-(1-(6-chloropyridazin-3-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4- 13fluorobenzyl)phthalazin-1(2H)-one6-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4- 14oxido-1,4-azaphosphinan-1-yl)nicotinonitrile4-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4- 15oxido-1,4-azaphosphinan-1-yl)benzonitrile2-(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4- 16oxido-1,4-azaphosphinan-1-yl)nicotinonitrile4-(3-(1-(2-chloropyrimidin-4-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4- 17fluorobenzyl)phthalazin-1(2H)-one4-(3-(1-(4-chloropyrimidin-2-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4- 18fluorobenzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(pyridin-2-yl)-1,4-azaphosphinan-4- 19yl)benzyl)phthalazin-1(2H)-one4-(3-(1-(3-chloro-5-(trifluoromethyl)pyridin-2-yl)-4-oxido-1,4- 20azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(quinazolin-4-yl)-1,4-azaphosphinan-4- 21yl)benzyl)phthalazin-1(2H)-one4-(3-(1-(6-chloropyrimidin-4-yl)-4-oxido-1,4-azaphosphinan-4-yl)-4- 22fluorobenzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(1-(3-fluoropyridin-2-yl)-4-oxido-1,4-azaphosphinan-4- 23yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(5-(trifluoromethyl)pyridin-2-yl)-1,4- 24azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(1-(6-fluoropyridin-2-yl)-4-oxido-1,4-azaphosphinan-4- 25yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(4-(trifluoromethyl)pyridin-2-yl)-1,4- 26azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(3-(trifluoromethyl)pyridin-2-yl)-1,4- 27azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(1-(3,5-difluoropyridin-2-yl)-4-oxido-1,4-azaphosphinan-4-28 yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(1-(5-fluoropyridin-2-yl)-4-oxido-1,4-azaphosphinan-4- 29yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(quinazolin-2-yl)-1,4-azaphosphinan-4- 30yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(6-(trifluoromethyl)pyridin-2-yl)-1,4- 31azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(thiazol-2-yl)-1,4-azaphosphinan-4- 32yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(thiadiazol-2-yl)-1,4-azaphosphinan-4- 33yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(3-(acetyl)pyridin-2-yl)-1,4-azaphosphinan-4-34 yl)benzyl)phthalazin-1(2H)-one(±)-4-(4-fluoro-3-(4-oxido-1-(3-(1-hydoxyethyl)pyridin-2-yl)-1,4- 35azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(5-(fluoro)pyrimidin-2-yl)-1,4-azaphosphinan-35 4-yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(5-(chloro)pyrimidin-2-yl)-1,4-azaphosphinan-36 4-yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(5-(n-propyl)pyrimidin-2-yl)-1,4- 37azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one4-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4- 38fluorobenzyl)phthalazin-1(2H)-one4-(3-(1-cyclobutyl-4-oxido-1,4-azaphosphinan-4-yl)-4- 39fluorobenzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(1-methyl-4-oxido-1,4-azaphosphinan-4- 40yl)benzyl)phthalazin-1(2H)-one4-(3-(1-ethyl-4-oxido-1,4-azaphosphinan-4-yl)-4- 41fluorobenzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(1-isopropyl-4-oxido-1,4-azaphosphinan-4- 42yl)benzyl)phthalazin-1(2H)-one4-(3-(1-(cyclopropylmethyl)-4-oxido-1,4-azaphosphinan-4-yl)-4- 43fluorobenzyl)phthalazine-1(2H)-one4-(4-fluoro-3-(1-isobutyl-4-oxido-1,4-azaphosphinan-4- 44yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-45propyl-1,4-azaphosphinan-4- 45yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(1-neopentyl-4-oxido-1,4-azaphosphinan-4- 46yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(1-neopentyl-4-oxido-1,4-azaphosphinan-4- 47yl)benzyl)phthalazin-1(2H)-one4-(4-fluoro-3-(1-isopentyl)-4-oxide-1,4-azaphosphinan-4- 48yl)benzyl)phthalazin-1(2H)-one4-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4- 49fluorobenzyl)phthalazin-1(2H)-one4-[[4-fluoro-3-(4-methyl-4-oxo-1,4-azaphosphinane-1- 50carbonyl)phenyl]methyl]-2H-phthalazin-1-one4-[[4-fluoro-3-(4-ethyl-4-oxo-1,4-azaphosphinane-1- 51carbonyl)phenyl]methyl]-2H-phthalazin-1-one4-[[4-fluoro-3-(4-isopropyl-4-oxo-1,4-azaphosphinane-1- 52carbonyl)phenyl]methyl]-2H-phthalazin-1-one4-[[4-fluoro-3-(4-ethoxyl-4-oxo-1,4-azaphosphinane-1- 53carbonyl)phenyl]methyl]-2H-phthalazin-1-one4-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)-7-54 fluorophthalazin-1(2H)-one4-[(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4- 55fluorophenyl)dideuteromethyl]-7-fluorophthalazin-1(2H)-one4-(4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4- 56yl)benzyl)-7-fluorophthalazin-1(2H)-one4-[(4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4- 57yl)phenyl)dideuteromethyl]-7-fluorophthalazin-1(2H)-one(±)-4-[(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluoro-1- 58phenyl)(hydroxymethl)]phthalazin-1(2H)-one(±)-4-{[4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4- 59yl)phenyl)](hydroxymethyl)]-7-fluorophthalazin-1(2H)-one

Pharmaceutical Compositions

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this invention. Thus, the invention includes pharmaceuticalcompositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. In one aspect, the pharmaceuticallyacceptable salt is an acid addition salt, such as a salt formed with aninorganic or organic acid. Pharmaceutical compositions according to theinvention may take a form suitable for oral, buccal, parenteral, nasal,topical or rectal administration or a form suitable for administrationby inhalation.

The present invention embraces the free base of compounds detailedherein, such as a compound of the formula (I), (II), (III), (IV), (V) orany variations thereof, as well as the pharmaceutically acceptable saltsand stereoisomers thereof. The compounds of the present invention can beprotonated at the N atom(s) of an amine and/or N containing heterocyclemoiety to form a salt. The term “free base” refers to the aminecompounds in non-salt form. The encompassed pharmaceutically acceptablesalts not only include the salts exemplified for the specific compoundsdescribed herein, but also all the typical pharmaceutically acceptablesalts of the free form of compounds detailed herein, such as a compoundof the formula (I), (II), (III), (IV), (V) or any variations thereof.The free form of the specific salt compounds described may be isolatedusing techniques known in the art. For example, the free form may beregenerated by treating a salt with a suitable dilute aqueous basesolution such as dilute aqueous NaOH, potassium carbonate, ammonia andsodium bicarbonate. The free base forms may differ from their respectivesalt forms somewhat in certain physical properties, such as solubilityin polar solvents, but the acid and base salts are otherwisepharmaceutically equivalent to their respective free forms for purposesof the invention.

The pharmaceutically acceptable salts of the instant compounds can besynthesized from the compounds of this invention which contain a basicor acidic moiety by conventional chemical methods. Generally, the saltsof the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of thisinvention include the conventional non-toxic salts of the compounds ofthis invention as formed by reacting a basic instant compound with aninorganic, organic acid or polymeric acid. For example, conventionalnon-toxic salts include those derived from inorganic acids such ashydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,sulfurous acid, sulfamic acid, phosphoric acid, phosphorous acid, nitricacid and the like, as well as salts prepared from organic acids such asacetic acid, propionic acid, succinic acid, glycolic acid, stearic acid,lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid,pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid,glutamic acid, benzoic acid, salicylic acid, sulfanilic acid,2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid,methanesulfonic acid, ethanesulfonic acid, ethylene disulfonic acid,oxalic acid, isethionic acid, palmitic acid, gluconic acid c, ascorbicacid, phenylacetic acid, aspartic acid, cinnamic acid, pyruvic acid,valeric acid, trifluoroacetic acid and the like. Examples of suitablepolymeric salts include those derived from the polymeric acids such astannic acid and carboxymethyl cellulose. Preferably, a pharmaceuticallyacceptable salt of this invention contains 1 equivalent of a compounddetailed herein, such as a compound of the formula (I), (II), (III),(IV), (V) or any variations thereof, and 1, 2 or 3 equivalent of aninorganic or organic acid. In some embodiments, the pharmaceuticallyacceptable salt contains 1 equivalent of a compound detailed herein,such as a compound of the formula (I), (II), (III), (IV), (V) or anyvariations thereof, and 1 equivalent of an inorganic or organic acid.

When the compound of the present invention is acidic, suitable“pharmaceutically acceptable salts” refers to salts prepared formpharmaceutically acceptable non-toxic bases including inorganic basesand organic bases. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium,manganic, manganous, potassium, sodium, zinc salts, and the like.Particularly preferred are the ammonium, calcium, magnesium, potassiumand sodium salts. Salts derived from pharmaceutically acceptable organicnon-toxic bases include salts of primary, secondary and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as arginine, lysine,betaine caffeine, choline, ethylamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,diethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylaminetripropylamine, tromethamine, dicyclohexylamine, butylamine,benzylamine, phenylbenzylamine, tromethamine, and the like.

General Synthetic Methods

Compounds of formula (I) may be prepared with procedures shown in Scheme1, where X is selected from Cl, Br, I, OTf, and carboxylic acid; andR^(A), R^(B), R^(C), R^(D), R^(E), and R^(P) are as defined in formula(I) or any variations described herein.

When X is selected from Cl, Br, I and OTf, compounds of formula I-1 cancouple with compounds of Formula I-2 under palladium catalyzed conditionto give compounds of Formula I where R^(P) is of Formula Ia.

Alternatively, when X is carboxylic acid, amide coupling of compounds ofFormula I-1 and phosphorus containing amines of Formula I-3 providescompounds of the formula (I) where R^(P) is of Formula Ib.

Compounds of Formula I-1 can be prepared according to the proceduresdisclosed in WO 2009/063244.

Compounds of Formula I-2 can be synthesized according to the methodillustrated in Scheme 2, where R′ is C₁-C₆ alkyl or aryl, and R^(D) isas defined in formula (I) or any variations described herein.

Commercially available compounds of Formula I-4 are reacted with 2 eq.of vinyl Grignard agent at low temperature to give rise to compound ofFormula I-5. Michael addition of an alkylamine R^(D)NH₂ to compounds ofFormula I-5 yields compounds of Formula I-6, which can be carefullyreduced by lithium aluminum hydride at low temperature (−20 to 0° C.) toafford compounds of Formula I-2. Compounds of Formula I-2 exist in twotautomeric forms.

Alternatively, compounds of Formula I-5 react with benzylamine to givecompounds of Formula I-7, which can be converted to compounds of FormulaI-8 with palladium-on-carbon catalyzed hydrogenolysis under pressure.Compounds of Formula I-6 with a variety of R^(D) can be prepared fromcompounds of Formula I-8, such as where R^(D) is —SO₂R³, —C(O)R⁴, aryland heteroaryl (from S_(N)Ar reaction or Pd catalyzed coupling), alkyl(via reductive amination).

Compounds of Formula I-3 can be prepared according to Scheme 3, whereR^(E) is as defined in formula (I) or any variations described herein.

Compounds of Formula I-9 are reacted with 2 eq. of vinyl Grignard agentat low temperature to give rise to compound of Formula I-10. Michaeladdition with benzylamine gives compounds of Formula I-11, which can beconverted to compounds of Formula I-3 with palladium-on-carbon catalyzedhydrogenolysis under pressure.

Compounds of Formula (II) may be prepared by reacting compound ofFormula II-1, or a compound of Formula II-2 with hydrazine, for example,as shown in Scheme 4, where R^(F), R^(C), and R^(P) are as defined informula (I) or any variations described herein.

The reaction is generally carried out in refluxing a hydrazine source,such as hydrazine monohydrate or hydrazine hydrate for 1-24 hours.

Compounds of Formula III may be prepared according to Scheme 5, where R″is a C₁-C₆ alkyl (e.g., Me, Et, i-Pr), and R^(F), R^(C), and R^(P) areas defined in formula (I) or any variations described herein.

A compound of the formula (III) can be prepared by reacting a compoundof Formula III-1 with a hydrazine source, such as hydrazine monohydrateor hydrazine hydrate, generally by refluxing for 1-24 hours.

Compounds of Formula III-1 may be synthesized by reacting a compound ofFormula III-2 and a compound of Formula III-3. The reaction is generallycarried out with a base, such as triethylamine or lithiumhexamethylsilazide in a solvent, such as THF, at temperature between−78° C. to refluxing.

Methods

Phosphorous containing heterocyclic compounds of the invention, such asphthalazin-1(2H)-one derivatives, are inhibitors of the enzymepoly(ADP-ribose)polymerase (PARP), previously known aspoly(ADP-ribose)synthase or poly(ADP-ribosyl)transferase. The compoundscan be used in a method of treatment of the human or animal body bytherapy.

The invention provides compounds for use in the treatment or preventionof conditions which can be ameliorated by the inhibition ofpoly(ADP-ribose)polymerase (PARP) (see, for example, Nature Review DrugDiscovery (2005) 4:421-440).

Thus, the present invention provides a compound, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof, foruse in the manufacture of a medicament for the treatment or preventionof conditions which can be ameliorated by the inhibition ofpoly(ADP-ribose)polymerase (PARP).

In some aspects, the compounds are useful as mono-therapies in tumorswith specific defects in DNA-repair pathways, such as cancers harboringPTEN, BRCA1, and BRCA2 mutations.

In some aspects, the compounds can act as enhancers of certainDNA-damaging chemotherapeutics such as anticancer alkylating agents,topoisomerase I inhibitors and radiotherapy.

In other aspects, the compounds may be useful for reducing cell necrosis(in stroke and myocardial infarction), down regulating inflammation andtissue injury, treating retroviral infections and protecting against thetoxicity of chemotherapy.

The present invention also provides a method for the treatment orprevention of conditions which can be ameliorated by the inhibition ofpoly(ADP-ribose)polymerase (PARP), which method comprises administrationto a patient in need thereof of an effective amount of a compounddetailed herein, such as a compound of the formula (I), (II), (III),(IV), (V) or any variations thereof, or a composition comprising acompound detailed herein, such as a compound of the formula (I), (II),(III), (IV), (V) or any variations thereof. In some embodiments, thecondition ameliorated by inhibition of PARP is a condition selected fromthe group consisting of cancer, inflammatory diseases, and ischemicconditions. In some embodiments, the cancer is a breast cancer, anovarian cancer or a brain cancer.

Most of the biological effects of PARP relate (1) topoly(ADP-ribosyl)ation process which influences the properties andfunction of the target proteins; (2) to the PAR oligomers that, whencleaved from poly(ADP-ribosyl)ated proteins, confer distinct cellulareffects: (3) to the physical association of PARP with nuclear proteinsto form functional complexes; and (4) to the lowering of the cellularlevel of its substrate NAD⁺ (Jagtap et al, Nature Review Drug Discovery(2005) 4:421-440).

Oxygen radical DNA damage, which is recognized by PARP, is a majorcontributing factor to such disease states as demonstrated by PARPinhibition (J Neurosci. Res. (1994) 39:38-46 and PNAS (1996)93:4688-4692).

The catalytic activity of PARP-1 and PARP-2 is stimulated by DNAbreakages (Tentori et al. Pharmacological Research (2005) 52:25-33). Inresponse to DNA damage, PARP-1 and PARP-2 bind to single and double DNAnicks. Under normal physiological conditions there is minimal PARPactivity; however, upon DNA damage PARP activity immediately increasesup to 500-fold. Both PARP-1 and PARP-2 detect DNA strand interruptionsacting as nick sensors, providing rapid signals to halt transcription,and subsequently recruit enzymes required for DNA repair at the site ofdamage. Since cancer therapies such as radiation and many cytotoxicagents act by inducing DNA damage, PARP inhibitors are useful as chemo-and radio-sensitizers for cancer treatment. For example, Löser et al.(Mol Cancer Ther. (2010) 9(6):1775-87) reported PARP inhibitors aseffective in radio sensitizing tumor cells.

PARP inhibitors are useful for the specific killing of BRCA-1 and BRCA-2deficient tumors (Bryant et al, Nature (2005) 434:913-916 and Farmer etal, Nature (2005) 434:917-921; and Cancer Biology & Therapy (2005)4:934-936; Drew et al, J Natl. Cancer Inst (2011) 103:1-13). Breastcancers with triple-negative status, i.e. lack of expression of estrogenreceptor-A and progesterone receptor, and lack of overexpression oramplification of the HER2/NEU oncogene, frequently harbor mutations inthe breast cancer susceptibility gene 1 (BRCA1). Breast cancer patientswith triple negative status have low response rate to currently approvedcancer therapies, but they may benefit from PARP inhibitors (Alli et al,Cancer Res (2009) 69(8):3589-96; Tutt et al, The Lancet (2010)376(9737):235-244).

In some embodiments, the invention provides a method for the treatmentor prevention of cancer, comprising administration to a patient in needthereof of an effective amount of a compound detailed herein, such as acompound of the formula (I), (II), (III), (IV), (V) or any variationsthereof, or a composition comprising a compound detailed herein, such asa compound of the formula (I), (II), (III), (IV), (V) or any variationsthereof. In some embodiments, the cancer is a cancer detailed below. Insome embodiments, the cancer is a breast cancer, an ovarian cancer or abrain cancer.

The compounds of this invention may also be useful for the treatment orprevention of cancer including solid tumors such as fibrosarcoma,myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma,angiosarcoma, endothelio sarcoma, lymphangiosarcoma,lymphangioendothelio sarcoma, synovioma, mesothelioma, Ewing's tumor,leiomyosarcoma, rhabdomyosarcoma, colon cancer, colorectal cancer,kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovariancancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer,nasal cancer, throat cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma. Wilms'tumor, cervical cancer, uterinecancer, testicular cancer, small cell lung carcinoma, bladder carcinoma,lung cancer, epithelial carcinoma, skin cancer, melanoma, neuroblastomaand retinoblastoma; blood-borne cancers such as acute lymphoblasticleukemia (“ALL”), acute lymphoblastic B-cell leukemia, acutelymphoblastic T-cell leukemia, acute myeloblasts leukemia (“AML”), acutepromyelocytic leukemia (“APL”), acute monoblastic leukemia, acuteerythro leukemic leukemia, acute megakaryoblastic leukemia, acutemyelomonocytic leukemia, acute nonlymphocytic leukemia, acuteundifferentiated leukemia, chronic myelocytic leukemia (“CML”), chroniclymphocytic leukemia (“CLL”), hairy cell leukemia and multiple myeloma;acute and chronic leukemias such as lymphoblastic, myelogenous,lymphocytic, myelocytic leukemias; lymphomas such as Hodgkin's disease,non-Hodgkin's Lymphoma, Multiple myeloma, Waldenstrom'smacroglobulinemia, Heavy chain disease and Polycythemia vera; and CNSand brain cancers such as glioma, pilocytic astrocytoma, astrocytoma,anaplastic astrocytoma, glioblastoma multiforme, medulloblastoma,craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acousticneuroma, oligodendroglioma, meningioma, vestibular schwannoma, adenoma,metastatic brain tumor, meningioma, spinal tumor and medulloblastoma.

Thus, the present invention provides a compound, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof, foruse in the manufacture of a medicament for the treatment or preventionof cancer, such as a cancer detailed herein (e.g., a breast cancer, anovarian cancer or a brain cancer).

The compounds of the present invention may also be used for thetreatment of cancer which is deficient in Homologous Recombination (HR)dependent DNA DSB repair activity (see WO 2006/021801). The HR dependentDNA DSB repair pathway repairs double-strand breaks (DSBs) in DNA viahomologous mechanisms to reform a continuous DNA helix (Nat. Genet.(2001) 27(3):247-254). The components of the HR dependent DNA DSB repairpathway include, but are not limited to, ATM, ATR, RAD51, RAD52, RAD54,DMC1, XRCC2, XRCC3, RAD52, RAD54L, RAD54B, BRCA-1, BRCA-2, RAD50, MREIIA, NBS1, ADPRT (PARP-1), ADPRTL2, (PARP-2) CTPS, RPA, RPA1, RPA2, RPA3,XPD5, ERCC1, XPF, MMS19, RAD51, XRCCR, XRCC3, BRCA1, BRCA2, RAD50.MRE11,NB51, WRN, BLMKU70, RU80, ATM, ATRCHK1, CHK2, FANCA, FANCB, FANCC,FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCC, FANCD1, FANCD2, FANCE,FANCF, FANCG, RAD1 and RAD9. Other proteins involved in the HR dependentDNA DSB repair pathway include regulatory factors such as EMSY (Cell(2003) 115:523-535).

A cancer which is deficient in HR dependent DNA DSB repair may compriseor consist of one or more cancer cells which have a reduced or abrogatedability to repair DNA DSBs through that pathway, relative to normalcells i.e. the activity of the HR dependent DNA DSB repair pathway maybe reduced or abolished in the one or more cancer cells.

The activity of one or more components of the HR dependent DNA DSBrepair pathway may be abolished in the one or more cancer cells of anindividual having a cancer which is deficient in HR dependent DNA DSBrepair. Components of the HR dependent DNA DSB repair pathway are wellcharacterized in the art (see for example, Science (2001) 291:1284-1289) and include the components listed above.

In some embodiments, the invention provides a method for the treatmentor prevention of cancer which is deficient in HR dependent DNA DSBrepair activity, comprising administration to a patient in need thereofof an effective amount of a compound detailed herein, such as a compoundof the formula (I), (II), (III), (IV), (V) or any variations thereof, ora composition comprising a compound detailed herein, such as a compoundof the formula (I), (TI), (III), (IV), (V) or any variations thereof.

The present invention also provides a compound, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof, foruse in the manufacture of a medicament for the treatment or preventionof a cancer which is deficient in HR dependent DNA DSB repair activity.

Some cancer cells have a BRCA1 and/or BRCA2 deficient phenotype. Cancercells with this phenotype may be deficient in BRCA1 and/or BRCA2, i.e.,expression and/or activity of BRCA1 and/or BRCA2 may be reduced orabolished in the cancer cells, for example by means of mutation orpolymorphism in the encoding nucleic acid, or by means of amplification,mutation or polymorphism in a gene encoding a regulatory factor, forexample the EMSY gene which encodes a BRCA2 regulatory factor (Cell(2003) 115:523-535). BRCA1 and BRCA2 are known tumor suppressors whosewild-type alleles are frequently lost in tumors of heterozygous carriers(Oncogene, (2002) 21(58):8981-93; Trends Mol. Med., (2002) 8(12):571-6).The association of BRCA1 and/or BRCA2 mutations with breast cancer hasbeen well-characterized (Exp Clin. Cancer Res., (2002) 21 (SSuppl.):9-12). Amplification of the EMSY gene, which encodes a BRCA-2binding factor, is also known to be associated with breast and ovariancancer. Carriers of mutations in BRCA-1 and/or BRCA-2 are also atelevated risk of cancer of the ovary, prostate and pancreas. Thedetection of variation in BRCA-1 and BRCA-2 is well-known in the art andis described, for example in Genet. Test (1992) 1:75-83; Cancer TreatRes (2002) 107:29-59; Neoplasm (2003) 50(4):246-50; Ceska Gynekol (2003)68(1): 11-16). Determination of amplification of the BRCA-2 bindingfactor EMSY is described in Cell 115:523-535. PARP inhibitors have beendemonstrated as being useful for the specific killing of BRCA-1 andBRCA-2 deficient tumors (Nature (2005) 434:913-916 and 917-920).

In some embodiments, the invention provides a method for the treatmentor prevention of BRCA-1 or BRCA-2 deficient tumors, comprisingadministration to an individual in need thereof of an effective amountof a compound detailed herein, such as a compound of the formula (I),(II), (III), (IV), (V) or any variations thereof or a compositioncomprising a compound detailed herein, such as a compound of the formula(I), (II), (III), (IV), (V) or any variations thereof.

Thus, the present invention provides a compound such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof, foruse in the manufacture of a medicament for the treatment or preventionof BRCA-I or BRCA-2 deficient tumors.

Some cancer cells have a mutated tumor suppressor gene, phosphatase andtensin homolog (PTEN). PTEN deficiency causes a homologous recombination(HR) defect in human tumor (Mendes-Pereira et al, EMBO Mol Med, (2009)1:315-322). PTEN is one of the most commonly mutated genes in humancancers. Recent evidence suggests that PTEN is important for themaintenance of genome stability cells (Shen et al, Cell (2007)128:157-170). The HR deficiency caused by PTEN deficiency, sensitizestumor cells to inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase (PARP), both in vitro and in vivo. PARP inhibitors arepotentially benefit to patients with PTEN mutant tumors (Dedes et al,Sci. Transl. Med. (2010) 2(53):53ra75; and McEllin Cancer Res. (2010)70(13):5457-64).

In some embodiments, the invention provides a method for the treatmentor prevention of PTEN mutated tumors, comprising administration to anindividual in need thereof of an effective amount of a compound detailedherein, such as a compound of the formula (I), (II), (III), (IV), (V) orany variations thereof or a composition comprising a compound detailedherein, such as a compound of the formula (I), (II), (III), (IV), (V) orany variations thereof.

Thus, the present invention provides a compound, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof, foruse in the manufacture of a medicament for the treatment or preventionof PTEN mutated tumors.

PARP inhibitors are effective for the treatment of inflammation diseases(Cuzzocrea, Pharmacological Research (2005) 52:72-82 and Virág,Pharmacological Research (2005) 52:83-92).

In some embodiments, the invention provides a method for the treatmentor prevention of inflammatory diseases, comprising administration to anindividual in need thereof of an effective amount of a compound detailedherein, such as a compound of the formula (I), (II), (III), (IV), (V) orany variations thereof or a composition comprising a compound detailedherein, such as a compound of the formula (I), (II), (III), (IV), (V) orany variations thereof.

The compounds of the invention are useful for the treatment ofinflammatory diseases, including conditions resulting from organtransplant rejection; chronic inflammatory diseases of the joints,including arthritis, rheumatoid arthritis; inflammatory bowel diseasessuch as ileitis, ulcerative colitis. Barrett's syndrome, and Crohn'sdisease; inflammatory lung diseases such as asthma, adult respiratorydistress syndrome, and chronic obstructive airway disease; inflammatorydiseases of the eye; chronic inflammatory diseases of the gum;inflammatory diseases of the kidney; inflammatory diseases of the skin;inflammatory diseases of the central nervous system; inflammatorydiseases of the heart such as cardiomyopathy, ischemic heart disease,and atherosclerosis; as well as various other diseases that can havesignificant inflammatory components, including preeclampsia, chronicliver failure, brain and spinal cord trauma.

The present invention also provides a compound, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof, foruse in the manufacture of a medicament for treating or preventinginflammatory diseases.

PARP enzymes may also act as a mediator of cell death. Its excessiveactivation in pathological conditions such as ischemia and reperfusioninjury can result in substantial depletion of the intercellular NAD⁺,which can lead to the impairment of several NAD⁺ dependent metabolicpathways and result in cell necrotic death (Devalaraja-Narashimha et al,Pharmacological Research (2005) 52:44-59). As a result of PARPactivation, NAD⁺ levels significantly decline. Extensive PARP activationleads to severe depletion of NAD⁺ in cells suffering from massive DNAdamage. The short half-life of poly(ADP-ribose) results in a rapidturnover rate, as once poly(ADP-ribose) is formed, it is quicklydegraded by the constitutively active poly(ADP-ribose) glycohydrolase(PARG). PARP and PARG form a cycle that converts a large amount of NAD⁺to ADP-ribose, causing a drop of NAD⁺ and ATP to less than 20% of thenormal level. Such a scenario is especially detrimental during ischemiawhen deprivation of oxygen has already drastically compromised cellularenergy output. Subsequent free radical production during reperfusion isassumed to be a major cause of tissue damage. Part of the ATP drop,which is typical in many organs during ischemia and reperfusion, couldbe linked to NAD⁺ depletion due to poly(ADP-ribose) turnover. Thus, PARPinhibition is expected to preserve the cellular energy level therebypotentiating the survival of ischemic tissues after insult. Compoundswhich are inhibitors of PARP are therefore useful for treatingconditions which result from PARP mediated cell death, includingneurological conditions such as stroke, trauma and Parkinson's disease.

PARP inhibitors are also useful in treating acute and chronic myocardialdiseases (Szabó, Pharmacological Research (2005) 52:34-43). Forinstance, single injections of PARP inhibitors reduced the infarct sizecaused by ischemia and reperfusion of the heart or skeletal muscle inrabbits (Thiemermann et al, PNAS (1997) 94:679-683). Similar findingshave also been reported in pigs (Eur. J. Pharmacol. (1998) 359:143-150and Ann. Thorac. Surg. (2002) 73:575-581), in dogs (Shock. (2004)21:426-32), and in rats (Bartha et al, J Cardiovasc. Pharmacol. 2008September; 52(3):253-61). PARP inhibitors were effective for treatingcertain vascular diseases, septic shock, ischemic injury andneurotoxicity (Biochim. Biophys. Acta (1989) 1014:1-7; J Clin. Invest.(1997) 100: 723-735).

In some embodiments, the invention provides a method for the treatmentor prevention of ischemic conditions and for the prevention or treatmentof stroke, comprising administration to an individual in need thereof ofan effective amount of a compound detailed herein, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof or acomposition comprising a compound detailed herein, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof.

The compounds of the instant invention may also be useful in thetreatment or prevention of ischemic conditions, including thoseresulting from organ transplantation, such as stable angina, unstableangina, myocardial ischemia, hepatic ischemia, mesenteric arteryischemia, intestinal ischemia, critical limb ischemia, chronic criticallimb ischemia, cerebral ischemia, acute cardiac ischemia, ischemiakidney disease, ischemic liver disease, ischemic retinal disorder,septic shock, and an ischemic disease of the central nervous system,such as stroke or cerebral ischemia.

Thus, the present invention provides a compound, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof, foruse in the manufacture of a medicament for the treatment or preventionof ischemic conditions, and for the treatment or prevention of stroke.

In some embodiments, the invention provides a method for the treatmentor prevention of reperfusion injuries, comprising administration to anindividual in need thereof of an effective amount of a compound detailedherein, such as a compound of the formula (I), (II), (III), (IV), (V) orany variations thereof or a composition comprising a compound detailedherein, such as a compound of the formula (I), (II), (III), (IV), (V) orany variations thereof.

The compounds of the instant invention may also be useful in thetreatment or prevention of reperfusion injuries, resulting fromnaturally occurring episodes and during a surgical procedure, such asintestinal reperfusion injury; myocardial reperfusion injury;reperfusion injury resulting from cardiopulmonary bypass surgery, aorticaneurysm repair surgery, carotid endarterectomy surgery, or hemorrhagicshock; and reoxygenation injury resulting from transplantation oforgans.

Thus, the present invention provides a compound, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof, foruse in the manufacture of a medicament for the treatment or preventionof reperfusion injuries.

The compounds of the instant invention may also be useful for thetreatment or prevention of chronic or acute renal failure.

In some embodiments, the invention provides a method for the treatmentor prevention of renal failure, comprising administration to anindividual in need thereof of an effective amount of a compound detailedherein, such as a compound of the formula (I), (II), (III), (IV), (V) orany variations thereof or a composition comprising a compound detailedherein, such as a compound of the formula (I), (II), (III), (IV), (V) orany variations thereof.

Thus, the present invention provides a compound, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof, foruse in the manufacture of a medicament for the treatment or preventionof renal failure.

PARP inhibition can efficiently block retroviral infection of mammaliancells. Such inhibition of recombinant retroviral vector infectionsoccurs in various different cell types (J Virology, (1996)70(6):3992-4000).

In some embodiments, the invention provides a method for the treatmentor prevention of an retroviral infection, comprising administration toan individual in need thereof of an effective amount of a compounddetailed herein, such as a compound of the formula (I), (II), (III),(IV), (V) or any variations thereof or a composition comprising acompound detailed herein, such as a compound of the formula (I), (II),(III), (IV), (V) or any variations thereof.

The invention also provides a compound, such as a compound of theformula (I), (II), (III), (IV), (V) or any variations thereof, for usein the manufacture of a medicament for the treatment or prevention of aretroviral infection.

PARP inhibitors have also found potential application in the treatmentor prevention of autoimmune diseases such as Type I diabetes anddiabetic complications, as demonstrated by in vitro and in vivoexperiments (Szabó, Pharmacological Research (2005) 52:60-71).

In some embodiments, the invention provides a method for the treatmentor prevention of an autoimmune disease (e.g., Type I diabetes),comprising administration to an individual in need thereof of aneffective amount of a compound detailed herein, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof or acomposition comprising a compound detailed herein, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof.

The invention also provides a compound, such as a compound of theformula (I), (II), (III), (IV), (V) or any variations thereof, for usein the manufacture of a medicament for the treatment or prevention of anautoimmune disease (e.g., Type I diabetes).

PARP plays an important role in controlling telomere function (NatureGen., (1999) 23:76-80), and thus PARP inhibition may delay the onset ofaging characteristics in human fibroblasts (Biochem. Biophys. Res. Comm.(1994) 201(2):665-672 and Bürkle et al, Pharmacological Research (2005)52:93-99).

In some embodiments, the invention provides a method for delaying theonset of aging, comprising administration to an individual in needthereof of an effective amount of a compound detailed herein, such as acompound of the formula (I), (II), (III), (IV), (V) or any variationsthereof or a composition comprising a compound detailed herein, such asa compound of the formula (I), (II), (III), (IV), (V) or any variationsthereof.

The invention also provides a compound, such as a compound of theformula (I), (II), (III), (IV), (V) or any variations thereof, for usein the manufacture of a medicament for delaying the onset of aging.

In another aspect, the invention provides a method for inhibiting PARP-1enzyme activity, comprising contacting PARP-1 enzyme with a compounddetailed herein, such as a compound of the formula (I), (II), (III),(IV), (V) or any variations thereof. In some embodiments, the compoundis capable of inhibiting PARP-1 enzymatic activity with an IC₅₀ of lessthan about 100 nM. In some embodiments, the compound has a PARP-1 enzymeinhibition IC₅₀ of less than about 1,000 nM, less than about 750 nM,less than about 500 nM, less than about 250 nM, less than about 150 nM,less than about 100 nM, less than about 50 nM, less than about 10 nM, orless than about 1 nM, as measured using the HT Universal ColorimetricPARP Assay Kit.

In another aspect, the invention provides a method for inhibitingintracellular poly(ADP-ribose) formation comprising contacting the cellwith a compound detailed herein, such as a compound of the formula (I),(II), (III), (IV), (V) or any variations thereof. In some embodiments,the compound is capable of inhibiting intracellular poly(ADP-ribose)formation with an EC₅₀ of less than about 100 nM. In some embodiments,the compound is capable of inhibiting intracellular poly(ADP-ribose)formation with an EC₅₀ of less than about 1,000 nM, less than about 750nM, less than about 500 nM, less than about 250 nM, less than about 150nM, less than about 100 nM, less than about 50 nM, less than about 10nM, or less than about 1 nM in C41 cells.

The compounds of this invention are capable of penetrating intact cellmembrane and inhibiting intracellular PARP enzymatic activities, thusinhibiting poly(ADP-ribose) formation catalyzed by PARP.

Administration

The compounds of this invention, such as a compound of the formula (I),(II), (III), (IV), (V) or any variations thereof, may be administered tomammals, preferably humans, either alone or in combination withpharmaceutically acceptable carriers, excipients, diluents, adjuvants,fillers, buffers, stabilizers, preservatives, lubricants, in apharmaceutical composition, according to standard pharmaceuticalpractice.

The compounds of this invention may be administered to a subject by anyconvenient route of administration, whether systemically/peripherally orat the site of desired action, including but not limited to, oral (e.g.by ingestion); topical (including e.g. transdermal, intranasal, ocular,buccal, and sublingual); pulmonary (e.g. by inhalation or insufflationtherapy using, e.g. an aerosol, e.g. through mouth or nose); rectal;vaginal; parenteral, (e.g. by injection, including subcutaneous,intradermal, intramuscular, intravenous, intraarterial, intracardiac,intrathecal, intraspinal, intracapsular, subcapsular, intraorbital,intraperitoneal, intratracheal, subcuticular, intraarticular,subarachnoid, and intrasternal); and by implant of a depot (e.g.subcutaneously or intramuscularly). The subject may be an animal or ahuman.

The invention also provides pharmaceutical compositions comprising oneor more compounds of this invention and a pharmaceutically acceptablecarrier. The pharmaceutical compositions containing the activeingredient may be in a form suitable for oral use, for example, astablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be, for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example,microcrystalline cellulose, sodium crosscarmellose, corn starch, oralginic acid; binding agents, for example starch, gelatin,polyvinyl-pyrolidone or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to mask the unpleasant taste ofthe drug or delay disintegration and absorption in the gastrointestinaltract and thereby provide a sustained action over a longer period. Forexample, a water soluble taste masking material such ashydroxypropyl-methylcellulose or hydroxypropylcellulose, or a time delaymaterial such as ethyl cellulose, cellulose acetate butyrate may beemployed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with watersoluble carrier such as polyethyleneglycol or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethyl-cellulose,sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose, saccharin or aspartame. Oily suspensions may beformulated by suspending the active ingredient in a vegetable oil, forexample arachis oil, olive oil, sesame oil or coconut oil, or in mineraloil such as liquid paraffin. The oily suspensions may contain athickening agent, for example beeswax, hard paraffin or cetyl alcohol.Sweetening agents such as those set forth above, and flavoring agentsmay be added to provide a palatable oral preparation. These compositionsmay be preserved by the addition of an anti-oxidant such as butylatedhydroxyanisol or alpha-tocopherol. Dispersible powders and granulessuitable for preparation of an aqueous suspension by the addition ofwater provide the active ingredient in admixture with a dispersing orwetting agent, suspending agent and one or more preservatives. Suitabledispersing or wetting agents and suspending agents are exemplified bythose already mentioned above. Additional excipients, for examplesweetening, flavoring and coloring agents, may also be present. Thesecompositions may be preserved by the addition of an anti-oxidant such asascorbic acid.

The pharmaceutical compositions of the invention may also be in the formof an oil-in-water emulsion. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally occurring phosphatides, for example soy bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example sorbitan monooleate, and condensation productsof the said partial esters with ethylene oxide, for examplepolyoxyethylene sorbitan monooleate. The emulsions may also containsweetening, flavoring agents, preservatives and antioxidants.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative, flavoring and coloring agentsand antioxidant.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous solution. Among the acceptable vehicles and solventsthat may be employed are water, Ringer's solution and isotonic sodiumchloride solution.

The sterile injectable preparation may also be a sterile injectableoil-in-water microemulsion where the active ingredient is dissolved inthe oily phase. For example, the active ingredient may be firstdissolved in a mixture of soybean oil and lecithin. The oil solutionthen introduced into a water and glycerol mixture and processed to forma microemulation.

The injectable solutions or microemulsions may be introduced into apatient's blood stream by local bolus injection. Alternatively, it maybe advantageous to administer the solution or microemulsion in such away as to maintain a constant circulating concentration of the instantcompound. In order to maintain such a constant concentration, acontinuous intravenous delivery device may be utilized.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension for intramuscular andsubcutaneous administration. This suspension may be formulated accordingto the known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example as a solution in 1,3-butanediol. In addition, sterile, fixedoils are conventionally employed as a solvent or suspending medium. Forthis purpose any bland fixed oil may be employed including syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid finduse in the preparation of injectables.

The compound, such as a compound of the formula (I), (II), (III), (IV),(V) or any variations thereof, may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritatingexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials include cocoa butter, glycerinated gelatin,hydrogenated vegetable oils, mixtures of polyethylene glycols of variousmolecular weights and fatty acid esters of polyethylene glycol.

For topical use, creams, ointments, jellies, solutions or suspensions,etc., containing the compound of Formula I are employed. (For purposesof this application, topical application shall include mouth washes andgargles.)

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles anddelivery devices, or via transdermal routes, using those forms oftransdermal skin patches well known to those of ordinary skill in theart. To be administered in the form of a transdermal delivery system,the dosage administration will, of course, be continuous rather thanintermittent throughout the dosage regimen. Compounds of the presentinvention may also be delivered as a suppository employing bases such ascocoa butter, glycerinated gelatin, hydrogenated vegetable oils,mixtures of polyethylene glycols of various molecular weights and fattyacid esters of polyethylene glycol. When a compound according to thisinvention is administered into a subject, the selected dosage level willdepend on a variety of factors including, but not limited to, theactivity of the particular compound, the severity of the individualssymptoms, the route of administration, the time of administration, therate of excretion of the compound, the duration of the treatment, otherdrugs, compounds, and/or materials used in combination, and the age,sex, weight, condition, general health, and prior medical history of thepatient. The amount of compound and route of administration willultimately be at the discretion of the physician, although generally thedosage will be to achieve local concentrations at the site of actionwhich achieve the desired effect without causing substantial harmful ordeleterious side-effects.

Administration in vivo can be effected in one dose, continuously orintermittently (e.g. in divided doses at appropriate intervals)throughout the course of treatment. Methods of determining the mosteffective means and dosage of administration are well known to those ofskill in the art and will vary with the formulation used for therapy,the purpose of the therapy, the target cell being treated, and thesubject being treated. Single or multiple administrations can be carriedout with the dose level and pattern being selected by the treatingphysician. Where the active compound is a salt, an ester, prodrug, orthe like, the amount administered is calculated on the basis of theparent compound and so the actual weight to be used is increasedproportionately.

Combination Therapy

The compounds of the invention, such as a compound of the formula (I),(II), (III), (IV), (V) or any variations thereof, are also useful incombination with other anti-cancer agents or chemotherapeutic agents.

PARP inhibitors can enhance the efficacy of anticancer drugs (Tentori etal, Pharmacological Research (2005) 52:25-33), including platinumcompounds such as cisplatin and carboplatin (Cancer Chemother. Pharmacol(1993) 33:157-162 and Mol Cancer Ther (2003) 2:371-382). PARP inhibitorshave been shown to increase the antitumor activity of topoisomerase Iinhibitors such as irinotecan and Topotecan (Mol Cancer Ther (2003)2:371-382; and Clin. Cancer Res (2000) 6:2860-2867; Daniel et al. Clin.Cancer Res (2009) 15(4):1241-1249) and this has been demonstrated in invivo models (J Natl. Cancer Inst. (2004) 96:56-67).

PARP inhibitors also can restore susceptibility to the cytotoxic andantiproliferative effects of temozolomide (TMZ) (Donawho et al, Clin.Cancer Res (2007) 13(9):2728-2737; Daniel et al, Clin. Cancer Res (2009)15(4):1241-1249); Menear et al, J. Med. Chem. (2008) 51:658146591).

PARP inhibitors can act as radiation sensitizers. PARP inhibitorssensitize radiation therapy in (hypoxic) tumor cells and enhance cellkilling by preventing tumor cells from recovering from potentiallylethal (Br. J. Cancer (1984) 49(Suppl. VI):34-42; and Int. J. RadialBiol. (1999) 75:91-100) and sub-lethal (Clin. Oncol. (2004) 16(1):29-39)damage of DNA after radiation therapy. The mechanism is presumably dueto their ability to prevent DNA strand break rejoining and by affectingseveral DNA damage signaling pathways.

The compounds of this invention may be useful as chemo- andradiosensitizers for cancer treatment. They are useful for the treatmentof mammals who have previously undergone or are presently undergoingtreatment for cancer. Such previous treatments include priorchemotherapy, radiation therapy, surgery or immunotherapy, such ascancer vaccines.

In some embodiments, provided is a combination comprising a compound,such as a compound of the formula (I), (II), (III), (IV), (V) or anyvariations thereof, and an second anti-cancer agent for simultaneous,separate or sequential administration. In some embodiments, provided isa pharmaceutical composition comprising a compound, such as a compoundof the formula (I), (II), (III), (IV), (V) or any variations thereof, ansecond anti-cancer agent, and a pharmaceutically acceptable carrier.

In some embodiments, the invention provides a combination of a compound,such as a compound of the formula (I), (II), (III), (IV), (V) or anyvariations thereof, a radiation therapy and another chemotherapeuticagent for simultaneous, separate or sequential administration.

The present invention also provides a compound, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof, foruse in the manufacture of a medicament for use as an adjunct in cancertherapy or for potentiating tumor cells by combination with ionizingradiation or chemotherapeutic agents.

The present invention also provides the use of a compound, such as acompound of the formula (I), (II), (III), (IV), (V) or any variationsthereof, in the manufacture of a medicament for use as an adjunct incancer therapy or for potentiating tumor cells by combination withionizing radiation and other chemotherapeutic agents. The compounds canalso be used in combination with ionizing radiation and otherchemotherapeutic agents.

The invention also provides a method of chemotherapy or radiotherapy,which method comprises administration to a patient in need thereof of aneffective amount of a compound detailed herein, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof, or acomposition comprising a compound detailed herein, such as a compound ofthe formula (I), (II), (III), (IV), (V) or any variations thereof, incombination with ionizing radiation or chemotherapeutic agents. Thecompounds can also be administered in combination with ionizingradiation and other chemotherapeutic agents.

In combination therapy, the compounds of this invention can beadministered prior to, concurrently with, or subsequent to theadministration of the other anticancer agent to a subject in needthereof.

The compounds of this invention and the other anticancer agent can actadditively or synergistically. A synergistic combination of the presentcompounds and another anticancer agent might allow the use of lowerdosages of one or both of these agents and/or less frequent dosages ofone or both of the instant compounds and other anticancer agents and/orto administer the agents less frequently can reduce any toxicityassociated with the administration of the agents to a subject withoutreducing the efficacy of the agents in the treatment of cancer. Inaddition, a synergistic effect might result in the improved efficacy ofthese agents in the treatment of cancer and/or the reduction of anyadverse or unwanted side effects associated with the use of either agentalone.

Examples of cancer agents or chemotherapeutic agents for use incombination with the compounds of the present invention can be found inCancer Principles and Practice of Oncology by V. T. Devita and S.Hellman (editors), 6th edition (2001), Lippincott Williams & WilkinsPublishers. A person of ordinary skill in the art would be able todiscern which combinations of agents would be useful based on theparticular characteristics of the drugs and the cancer involved. Suchanti-cancer agents include, but are not limited to, the following: HDACinhibitors, estrogen receptor modulators, androgen receptor modulators,retinoid receptor modulators, cytotoxic/cytostatic agents,antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoAreductase inhibitors, HIV protease inhibitors, reverse transcriptaseinhibitors and other angiogenesis inhibitors, inhibitors of cellproliferation and survival signaling, apoptosis inducing agents andagents that interfere with cell cycle checkpoints. The instant compoundsare particularly useful when co-administered with radiation therapy.

Examples of “HDAC inhibitors” include suberoylanilide hydroxamic acid(SAHA), LAQ824, LBH589, PXDIO1, MS275, FK228, valproic acid, butyricacid and CI-994.

“Estrogen receptor modulators” refers to compounds that interfere withor inhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, tamoxifen, raloxifene, idoxifene, LY353381, LY1 17081,toremifene, fulvestrant, and SH646.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate, MDV3100.

“Retinoid receptor modulators” refers to compounds which interfere orinhibit the binding of retinoids to the receptor, regardless ofmechanism. Examples of such retinoid receptor modulators includebexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid.CC-difluoromethylomithine, TLX23-7553.

“Cytotoxic/cytostatic agents” refer to compounds which cause cell deathor inhibit cell proliferation primarily by interfering directly with thecell's functioning or inhibit or interfere with cell mytosis, includingalkylating agents, tumor necrosis factors, intercalators, hypoxiaactivatable compounds, microtubule inhibitors/microtubule-stabilizingagents, inhibitors of mitotic kinesins, inhibitors of kinases involvedin mitotic progression, antimetabolites, biological response modifiers;hormonal/anti-hormonal therapeutic agents, hematopoietic growth factors,monoclonal antibody targeted therapeutic agents, topoisomeraseinhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.

Examples of cytotoxic agents include, but are not limited to,cyclophosphamide, chlorambucil carmustine (BCNU), lomustine (CCNU),busulfan, treosulfan, sertenef, cachectin, ifosfamide, tasonermin,lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol,ranimustine, fotemustine, nedaplatin, aroplatin, oxaliplatin,temozolomide, methyl methanesulfonate, procarbazine, dacarbazine,heptaplatin, estramustine, improsulfan tosilate, trofosfamide,nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin,profiromycin, cisplatin, irofulven, dexifosfamide,cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine,glufosfamide, GPX1OO. (trans, trans,trans)-bis-mu-(hexane-1,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum(II)]tetrachloride, diarizidinylspermine, arsenic trioxide,1-(11-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin,idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin,pinafide, valrubicin, amrubicin, doxorubicin, epirubicin, pirarubicin,antineoplaston,3′-deamino-3′-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin,galarubicin, elinafide, MEN 10755 and4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (seeWO 00/50032). Further examples include Raf kinase inhibitors (such asBay43-9006) and mTOR inhibitors (such as Wyeth's CCI-779 and AriadAP23573). Further examples are inhibitors of PBK (for example LY294002).In an embodiment the compounds of this invention can be used incombination with alkylating agents.

Examples of alkylating agents include but are not limited to, nitrogenmustards: cyclophosphamide, ifosfamide, trofosfamide and chlorambucil;nitrosoureas: carmustine (BCNU) and lomustine (CCNU); alkylsulphonates:busulfan and treosulfan; triazenes: dacarbazine, procarbazine andtemozolomide; platinum containing complexes: cisplatin, carboplatin,aroplatin and oxaliplatin.

Examples of anti-mitotic agents include: allocolchicine, halichondrin B,colchicine, colchicine derivative, dolstatin 10, maytansine, rhizoxin,thiocolchicine and trityl cysteine. An example of a hypoxia activatablecompound is tirapazamine.

Examples of proteasome inhibitors include but are not limited tolactacystin, bortezomib, epoxomicin and peptide aldehydes such as MG132, MG 115 and PSI.

Examples of microtubule inhibitors/microtubule-stabilizing agentsinclude paclitaxel, vindesine sulfate, vincristine, vinblastine,vinorelbine, 3′,4′-didehydro-4′-deoxy-8′-norvincaleukoblastine,docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin,cemadotin, RPR109881, BMS184476, vinfiunine, cryptophycin, TDX258, theepothilones (see for example U.S. Pat. Nos. 6,284,781 and 6,288,237) andBMS 188797. Some examples of topoisomerase inhibitors are topotecan,hycaptamine, irinotecan, rubitecan, exatecan, gimetecan, difiomotecan,silyl-camptothecins, 9-aminocamptothecin, camptothecin, crisnatol,mitomycin C, lurtotecan, BNP1350, BNPII 1OO, BN80915. BN80942, etoposidephosphate, teniposide, sobuzoxane, 2′-dimethylamino-2′-deoxy-etoposide,GL331, asulacrine, and dimesna; non-camptothecin topoisomerase-1inhibitors such as indolocarbazoles; and dual topoisomerase-1 and IIinhibitors such as benzophenazines, XR20 115761, MLN 576 andbenzopyridoindoles.

In an embodiment inhibitors of mitotic kinesins include, but are notlimited to inhibitors of KSP, inhibitors of MKLP1, inhibitors of CENP-E,inhibitors of MCAK, inhibitors of Kif14, inhibitors of Mphosph1 andinhibitors of Rab6-KIFL.

“Inhibitors of kinases involved in mitotic progression” include, but arenot limited to, inhibitors of aurora kinase, inhibitors of Polo-likekinases (PLK) (in particular inhibitors of PLK-I), inhibitors of bub-1and inhibitors of bub-R1.

“Antiproliferative agents” includes antisense RNA and DNAoligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001,and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin,doxifluridine, trimetrexate, fiudarabine, capecitabine, galocitabine,cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed,paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed,nelzarabine, 2′-deoxy-2′-methylidenecytidine,2′-fluoromethylene-2′-deoxycytidine, aplidine, ecteinascidin,troxacitabine, aminopterin, 5-flurouracil, alanosine, swainsonine,lometrexol, dexrazoxane, methioninase, and3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Examples of monoclonal antibody targeted therapeutic agents includethose therapeutic agents which have cytotoxic agents or radioisotopesattached to a cancer cell specific or target cell specific monoclonalantibody. Examples include Bexxar.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductaseinhibitors that may be used include but are not limited to lovastatin,simvastatin, pravastatin, faivastatin, and atorvastatin. The termHMG-CoA reductase inhibitor as used herein includes all pharmaceuticallyacceptable lactone and open-acid forms (i.e., where the lactone ring isopened to form the free acid) as well as salt and ester forms ofcompounds which have HMG-CoA reductase inhibitory activity, andtherefore the use of such salts, esters, open-acid and lactone forms isincluded within the scope of this invention.

“Prenyl-protein transferase inhibitor” refers to a compound whichinhibits any one or any combination of the prenyl-protein transferaseenzymes, including farnesyl-protein transferase (FPTase),geranylgeranyl-protein transferase type I (GGPTase-1), andgeranylgeranyl-protein transferase type-II (GGPTase-II, also called RabGGPTase).

“Angiogenesis inhibitors” refers to compounds that inhibit the formationof new blood vessels, regardless of mechanism. Examples of angiogenesisinhibitors include, but are not limited to, tyrosine kinase inhibitors,such as inhibitors of the tyrosine kinase receptors FIt-1 (VEGFR1) andFlk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived,or platelet derived growth factors, MMP (matrix metalloprotease)inhibitors, integrin blockers, interferon-α, interleukin-12, pentosanpolysulfate, cyclooxygenase inhibitors, including nonsteroidalantiinflammatories (NSAIDs) like aspirin and ibuprofen as well asselective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib(PNAS (1992) 89:7384; J Mol. Endocrinol. (1996) 16:107; Jpn. J.Pharmacol. (1997) 75:105; Cancer Res (1991) 57:1625; Cell (1998) 93:705;Intl. J. Mol. Med. (1998) 2:715; J Biol. Chem. (1999) 274:9116,steroidal antiinflammatories (such as corticosteroids,mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred,betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine,thalidomide, angiostatin, troponin-1, angiotensin II antagonists (see J.Lab. Clin. Med. (1985) 105:141-145), and antibodies to VEGF (see NatureBiotechnology (1999) 17:963-968; Kim et al (1993) Nature 362:841-844; WO00/44777; and WO 00/61186).

“Agents that interfere with cell cycle checkpoints” refer to compoundsthat inhibit protein kinases that transduce cell cycle checkpointsignals, thereby sensitizing the cancer cell to DNA damaging agents.Such agents include inhibitors of ATR, ATM, the Chk1 and Chk2 kinasesand cdk and cdc kinase inhibitors and are specifically exemplified byflavopiridol, CYC202 (Cyclacel), LY2606368, and BMS-387032.

“Inhibitors of cell proliferation and survival signaling pathway” referto pharmaceutical agents that inhibit cell surface receptors and signaltransduction cascades downstream of those surface receptors. Such agentsinclude inhibitors of EGFR and or HER2 (for example gefitinib,erlotinib, lapatinib, and trastuzumab), inhibitors of IGFR, inhibitorsof cytokine receptors, inhibitors of MET, inhibitors of PI3K, inhibitorsof serine/threonine kinases, inhibitors of Raf kinase (for examplePLX-4032 and PLX-4720), inhibitors of MEK (for example AZD6244, CI-1040and PD-098059) and inhibitors of mTOR (for example Everolimus and AriadAP23573). Such agents include small molecule inhibitor compounds andantibody antagonists.

“Apoptosis inducing agents” include activators of TNF receptor familymembers (including the TRAIL receptors).

In an embodiment the compounds of the present invention, such as acompound of the formula (I), (II), (III), (IV), (V) or any variationsthereof, are useful for treating cancer in combination with one or more,particularly one, two or three agents selected from temozolomide,cisplatin, carboplatin, oxaliplatin, irinotecan and topotecan.

A compound of the instant invention may also be useful for treatingcancer in combination with any one or more of the following therapeuticagents: abarelix (Plenaxis Depot®); aldesleukin (Prokine®); Aldesleukin(Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®);allopurinol (Zylopriin®); altretamine (Hexalen®); amifostine (Ethyol®);anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase(Elspar®); azacitidine (Vidaza®); bevacuzimab (Avastin®); bexarotenecapsules (Targretin®); bexarotene gel (Targretin®); bleomycin(Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®);busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine(Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®);carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (GliadelWafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil(Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®);clofarabine (Clolarf); cyclophosphamide (Cytoxan®, Neosar®);cyclophosphamide (Cytoxan Injection®); cyclophosphamide (CytoxanTablet®); cytarabine (Cytosar-U®); cytarabine liposomal (DepoCyt®);dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®);Darbepoetin alfa (Aranesp®); daunorubicin liposomal (DanuoXome®);daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin(Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®);docetaxel (Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin(Adriamycin®, Rubex®); doxorubicin (Adriamycin PFS Injection®);doxorubicin liposomal (Doxil®); dromostanolone pmpionate(Dromostanolone®); dromostanolone propionate (Masterone Injection®);Elliott's B Solution (Elliott's B Solution®); epirubicin (Ellence®);Epoetin alfa (Epogen®); erlotinib (Tarceva®); estramustine (Emcyt®);etoposide phosphate (Etopophos®); etoposide, VP-16 (Vepesid®);exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine(intraarterial) (FUDR®); fludarabine (Fludara®); fluorouracil, 5-FU(Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine(Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (ZoladexImplant®); goserelin acetate (Zoladex®); histrelin acetate (HistrelinImplant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®);idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate(Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (IntronA®); irinotecan (Camptosar®); lenalidomide (Revlimid®); letrozole(Femara®); leucovorin (Wellcovorin®. Leucovorin®); Leuprolide Acetate(Eligard®); levamisole (Ergamisol®); lomustine. CCNU (CeeBU®);meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate(Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP(Purinethol®); mesna (Mesnex®); mesna (Mesnex Tabs®); methotrexate(Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®);mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolonephenpropionate (Durabolin-50®); nelarabine (Arranon®); Nofetumomab(Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel(Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles(Abraxane®); palifermin (Kepivance®); pamidronate (Aredia®); pegademase(Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim(Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®);pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimersodium (Photofrin®); procarbazine (Matulane®); quinacrine (Atabrine®);Rasburicase (Elitek®); Rituximab (Rituxan®); sargramostim (Leukine®);Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®);sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®);temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone(Teslac®); thioguanine, 6-TG (Thioguanine®); thiotepa (Thioplex®);topotecan (Ilycamtin®); toremifene (Fareston®); Tositumomab (Bexxar);Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®);tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®);valrubicin (Valstar); vinblastine (Velban®); vincristine (Oncovin®);vinorelbine (Navelbine®); vorinostat (Zolinza®); zoledronate (Zometa®);nilotinib (Tasigna®) and dasatinib (Sprycel®).

Another embodiment of the instant invention is the use of the compoundsdetailed herein, such as a compound of the formula (I), (II), (III),(IV), (V) or any variations thereof, in combination with anti-viralagents (such as nucleoside analogs including ganciclovir for thetreatment of cancer.

Another embodiment of the instant invention is the use of the compoundsdetailed herein, such as a compound of the formula (I), (II), (III),(IV), (V) or any variations thereof, in combination with gene therapyfor the treatment of cancer. For an overview of genetic strategies totreating cancer see Hall et al (Am J Hum Genet (1997) 61:785-789) andKufe et al (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton2000). Gene therapy can be used to deliver any tumor suppressing gene.Examples of such genes include, but are not limited to, p53, which canbe delivered via recombinant virus-mediated gene transfer, a uPA/uPARantagonist (“Adenovirus-Mediated Delivery of a uPA/uPAR AntagonistSuppresses Angiogenesis-Dependent Tumor Growth and Dissemination inMice,” Gene Therapy, August (1998) 5(8): 1105-13), and interferon gamma(J. Immunol. (2000) 164:217-222).

The compounds of the instant invention, such as a compound of theformula (I), (II), (III), (IV), (V) or any variations thereof, may alsobe administered in combination with an inhibitor of inherent multidrugresistance (MDR), in particular MDR associated with high levels ofexpression of transporter proteins. Such MDR inhibitors includeinhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576,OC144-093, R101922, VX853, verapamil and PSC833 (valspodar).

A compound of the present invention, such as a compound of the formula(I), (II), (III), (IV), (V) or any variations thereof, may be employedin conjunction with anti-emetic agents to treat nausea or emesis,including acute, delayed, late-phase, and anticipatory emesis, which mayresult from the use of a compound of the present invention, alone orwith radiation therapy. For the prevention or treatment of emesis, acompound of the present invention may be used in conjunction with otheranti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3receptor antagonists, such as ondansetron, granisetron, tropisetron, andzatisetron, GABA B receptor agonists, such as baclofen, a corticosteroidsuch as Decadron (dexamethasone), Kenalog. Aristocort, Nasalide,Preferid, Benecorten, an antidopaminergic, such as the phenothiazines(for example prochlorperazine, fluphenazine, thioridazine andmesoridazine), metoclopramide or dronabinol. In an embodiment, ananti-emesis agent selected from a neurokinin-1 receptor antagonist, a5HT3 receptor antagonist and a corticosteroid is administered as anadjuvant for the treatment or prevention of emesis that may result uponadministration of the instant compounds.

A compound of the instant invention, such as a compound of the formula(I), (II), (III), (IV), (V) or any variations thereof, may also beadministered with an agent useful in the treatment of anemia. Such ananemia treatment agent is, for example, a continuous eythropoiesisreceptor activator (such as epoetin alfa).

A compound of the instant invention, such as a compound of the formula(I), (II), (III), (IV), (V) or any variations thereof, may also beadministered with an agent useful in the treatment of neutropenia. Sucha neutropenia treatment agent is, for example, a hematopoietic growthfactor which regulates the production and function of neutrophils suchas a human granulocyte colony stimulating factor, (G-CSF). Examples of aG-CSF include filgrastim.

A compound of the instant invention, such as a compound of the formula(I), (II), (III), (IV), (V) or any variations thereof, may also beadministered with an immunologic-enhancing drug, such as levamisole,isoprinosine and Zadaxin.

A compound of the instant invention, such as a compound of the formula(I), (II), (III), (IV), (V) or any variations thereof, may also beuseful for treating or preventing cancer, including bone cancer, incombination with Xgeva™ (denosumab), or with bisphosphonates (understoodto include bisphosphonates, diphosphonates, bisphosphonic acids anddiphosphonic acids). Examples of bisphosphonates include but are notlimited to: etidronate (Didronel), pamidronate (Aredia), alendronate(Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate(Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate,neridronate, piridronate and tiludronate including any and allpharmaceutically acceptable salts, derivatives, hydrates and mixturesthereof.

The invention encompasses the use of the compounds detailed herein, suchas a compound of the formula (I), (II), (III), (IV), (V) or anyvariations thereof, in combination with ionizing radiation and/or incombination with a second compound selected from: HDAC inhibitors, anestrogen receptor modulator, an androgen receptor modulator, retinoidreceptor modulator, a cytotoxic/cytostatic agent, an antiproliferativeagent, a prenyl-protein transferase inhibitor, an HMG-CoA reductaseinhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR-dagonist, an anti-viral agent, an inhibitor of inherent multidrugresistance, an anti-emetic agent, an agent useful in the treatment ofanemia, an agent useful in the treatment of neutropenia, animmunologic-enhancing drug, an inhibitor of cell proliferation andsurvival signaling, an agent that interferes with a cell cyclecheckpoint, an apoptosis inducing agent and a bisphosphonate.

Also included in the scope of the claims is a method of treating cancerthat comprises administering a therapeutically effective amount of acompound detailed herein, such as a compound of the formula (I), (II),(III), (IV), (V) or any variations thereof, in combination withradiation therapy and/or in combination with a compound selected from:HDAC inhibitors, an estrogen receptor modulator, an androgen receptormodulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, anantiproliferative agent, a prenyl-protein transferase inhibitor, anHMG-CoA reductase inhibitor, an angiogenesis inhibitor, a PPAR-γagonist, a PPAR-δ agonist, an anti-viral agent, an inhibitor of inherentmultidrug resistance, an anti-emetic agent, an agent useful in thetreatment of anemia, an agent useful in the treatment of neutropenia, animmunologic-enhancing drug, an inhibitor of cell proliferation andsurvival signaling, an agent that interferes with a cell cyclecheckpoint, an apoptosis inducing agent and a bisphosphonate.

EXAMPLES

The invention can be further understood by reference to the followingexamples, which are provided by way of illustration and are not meant tobe limiting.

Abbreviations used in the description of the chemistry and in theExamples that follow are: AcCl (acetyl chloride); Cbz-Cl(benzylchloroformate); DCM (dichloromethane); DIPEA(diisopropylethylamine); DMF (dimethylformamide); DMSO (dimethylsulfoxide); eq. (equivalent); EtOAc (ethyl acetate); EtOH (ethanol);mol. sieves (molecular sieves); HATU[(7-azabenzotriazol-1-yl)-tetramethyluronium hexafluorophosphate]; MeCN(acetonitrile); MeOH (methanol); MS (mass spectrometry); MW (microwave);NBS (N-bromosuccinimide); NMR (nuclear magnetic resonance); iPrOH(isopropanol); RT (room temperature); sat. aq. (saturated aqueous); SiO₂(silica gel); and THF (tetrahydrofuran), t-BuOH (tert-butanol); TLC(thin layer chromatography) and TFA (trifluoroacetic acid).

Example 14-(3-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one

Step 1.1: Synthesis of 1-benzyl-4-ethoxy-1,4-azaphosphinane 4-oxide(1.1)

Compound 1.1 was made from ethyl divinylphophinate (Maier, L. Helv.Chim. Acta 1971, 54, 275), and followed by coupling with benzyl amine inrefluxing ethanol (Dunne et al. J. Org. Chem., 2005, 70, 10803-10809),as disclosed in literature.

Step 1.2: Synthesis of 1-benzyl-1,4-azaphosphinane 4-oxide (1.2)

A 2M solution of lithium aluminum hydride in THF (3.16 mL, 6.32 mmol)was added dropwise to a stirring solution of 1.1 (2.00 g, 7.90 mmol) inTHF (30 mL) at 0° C. over the course of 5 min. After stirring for 45 minat 0° C., H₂O (300 μL) was added very slowly dropwise, followed by 15%NaOH (300 μL), then H₂O (900 μL). The resulting slurry was stirred for 1h at r.t., filtered, cake washed with THF (200 mL), and the filtratesconcentrated to give a crude semisolid. Column chromatography using0-30% (gradient) MeOH/DCM afforded product 7 as a yellow oil (1.20 g,72.6%).

Step 1.3: Synthesis of dimethyl3-oxo-1,3-dihydroisobenzofuran-1-ylphosphonate (1.3)

Dimethyl phosphite (100 g, 0.909 mol) was added dropwisely at 0° C.under nitrogen to a stirred solution of sodium methoxide (0.909 mol) inmethanol (800 ml). After completion of the addition, the reactionmixture was stirred for another 5 minutes, and 2-carboxybenzaldehyde(95.5 g, 0.64 mol) was added in 5 portions over 0.5 h. The stirredmixture was allowed to warm to room temperature, then it was stirred foranother 30 minutes. The reaction was then cooled in ice, andmethanesulfonic acid (96 g, 1.0 mol) was added in portions, while keepthe reaction temperature under 10° C. The solvent was removed in vacuo.The residue was partitioned between DCM (1.8 L) and water (0.45 L), andthe organic layer was separated, washed with water (2×450 mL) and dried(MgSO4). The solvent was removed in vacuo, the residue was trituratedwith ether (150 mL). The resulting solid was collected by filtration,washed with ether (30 ml) and dried in vacuo to give 1.3 (140 g) as awhite crystalline solid. ¹H NMR (250 MHz, DMSO-d6) δ (ppm): 3.65 (d,3H), 3.85 (d, 3H), 6.4 (d, 1H), 7.75 (m, 2H), 7.85-8.05 (m, 2H); LCMS,m/z (M+H): 243.

Step 1.4: Synthesis of3-(3-bromo-4-fluorobenzylidene)isobenzofuran-1(3H)-one (1.4)

TEA (2.11 mL, 15.17 mmol) was added dropwise to a stirring solution of3-bromo-4-fluorobenzaldehyde (3.08 g, 15.17 mmol) and compound 1.3 (3.67g, 15.17 mmol) in THF (40 mL) at 0° C. The reaction mixture warmed tor.t. and stirred overnight, concentrated and the residue was slurried inH₂O (300 mL) for 1 h, filtered, washed with H₂O (2×150 mL), hexane(2×100 mL), ether (2×150 mL), and dried to give 1.4 as a white powder(3.80 g, 78.5%).

Step 1.5: Synthesis of 4-(3-bromo-4-fluorobenzyl)phthalazin-1(2H)-one(1.5)

Aqueous NaOH (13 N, 4.25 mL) was added to a suspension of 1.4 (3.80 g,11.91 mmol) in H₂O (60 mL) at rt. The mixture was stirred at 90° C. for1 h, cooled to 70° C., added hydrazine monohydrate (8.11 mL, 116.70mmol) slowly, and stirred at 90° C. overnight. The reaction mixture wascooled to r.t., acidified to pH ˜4 with conc. HCl, filtered, washed withH₂O (2×150 mL), sonicated in ether (200 mL), filtered, washed with ether(100 mL) and dried to afford 1.5 as a white powder (3.17 g, 79.9%).

Step 1.6: Synthesis of4-(3-(1-benzyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(1)

Palladium (II) acetate (386 mg, 1.72 mmol) and1,3-bis(diphenylphosphino)propane (710 mg, 1.72 mmol) were stirred inDMF (30 mL) for 15 min. A solution of 10 (3.82 g, 11.47 mmol), 7 (2.40g, 11.47 mmol), and DIPEA (10 mL, 57.36 mmol) in DMF (30 mL) was addedand the reaction mixture stirred at 120° C. overnight. Afterconcentrating, column chromatography using 0-10% (gradient) MeOH/DCMgave a light yellow semisolid, which was diluted in DCM (100 mL), washedwith H₂O (2×100 mL), the aqueous layer was extracted with DCM (100 mL),combined organic layer was then washed with brine (100 mL), dried overMgSO₄, concentrated, sonicated in ether and filtered to afford 1 as apale yellow solid (3.27 g, 61.8%). ¹H NMR (CD₃OD, 300 MHz) δ 8.35 (d,1H), 7.95 (d, 1H), 7.82 (m, 3H), 7.65 (m, 1H), 7.32 (m, 3H), 7.24 (m,3H), 4.43 (s, 2H), 3.66 (s, 2H), 2.94 (m, 8H), 2.42 (m, 2H), 2.07 (t,2H). MS (ESI) m/z=462.2 (MH⁺).

Example 24-(3-(1-(cyclopentanecarbonyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one

Step 2.1: Synthesis of4-(4-fluoro-3-(4-oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one hydrochloride (2.1)

A mixture of compound 1 (1.00 g, 2.17 mmol), 4M HC in 1,4-dioxane (2mL), and Pd(OH)₂/C (20% wt. wet, 1 g) in MeOH (30 mL) was hydrogenatedunder 60 psi H₂ overnight. The reaction mixture was filtered throughCelite, washed with warm MeOH (100 mL), and combined filtrates wereconcentrated and lyophilized to give 2.1 as a pale pink hydrochloridesalt (800 mg, 90.5%). ¹H NMR (CD₃OD, 300 MHz) δ 8.35 (d, 1H), 7.95 (d,1H), 7.84 (m, 3H), 7.66 (m, 1H), 7.22 (m, 1H), 4.40 (s, 2H), 3.21 (m,2H), 2.91 (m, 2H), 2.40 (m, 3H), 2.09 (m, 2H). LCMS (ESI+) m/z=372.1(M+H).

Step 2.2: Synthesis of4-(3-(1-(cyclopentanecarbonyl)-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(2)

Cyclopentanecarbonyl chloride (16 μL, 0.13 mmol) was added to a solutionof 2.1 (43.9 mg, 0.11 mmol) and DIPEA (28 μL, 0.16 mmol) in DCM (1 mL)at 0° C. and the reaction mixture was stirred for 1 h. The concentratedresidue was subjected to prep-TLC using 10% MeOH/DCM and lyophilized togive 2 as a white powder (38 mg, 75.5%). ¹H NMR (CD₃OD, 300 MHz) δ 8.35(d, 1H), 7.95 (d, 1H), 7.84 (m, 3H), 7.66 (m, 1H), 7.22 (m, 1H), 4.55(m, 1H), 4.43 (s, 2H), 4.32 (m, 1H), 3.91 (m, 1H), 3.50 (m, 1H), 3.14(m, 1H), 2.38 (m, 2H), 2.15 (m, 2H), 1.76 (m, 8H). LCMS (ESI+) m/z=468.2(M+H).

Examples 3-10

LCMS Example ¹H NMR(300 MHz) m/z No. R^(D) Chemical Name (Solvent) δ ppm(M + H) 3

4-(3-(1- (cyclopropanecarbonyl)- 4-oxido-1,4- azaphosphinan-4-yl)-4-fluorobenzy)phthalazin- 1(2H)-one (DMSO-d6) 12.58 (s, 1H), 8.24 (d, 1H),8.00 (d, 1H), 7.82 (m, 3H), 7.62 (m. 1H), 7.28 (m, 1H), 4.39 (s, 2H),4.24 (m, 2H), 3.85 (m, 1H), 2.08 (m, 6H), 0.74 (m, 4H). 441 4

4-(3-(1- (cyclobutanecarbonyl)-4- oxido-1,4- azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin- 1(2H)-one (DMSO-d6) 12.58 (s, 1H), 8.24 (d,1H), 8.00 (d, 1H), 7.82 (m, 3H), 7.60 (m, 1H), 7.27 (m, 1H), 4.38 (s,2H), 4.17 (m, 2H), 3.64 (m, 3H), 2.08 (m, 8H), 1.74 (m, 2H). 455 5

4-(3-(1-(3,3- dimethylbutanoyl)-4- oxido-1,4- azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin- 1(2H)-one (DMSO-d6) 12.58 (s, 1H), 8.24 (d,1H), 8.00 (d, 1H), 7.82 (m, 3H), 7.61 (m, H), 7.28 (m, 1H), 4.38 (m,2H), 4.28 (m, 2H), 4.00 (m. 2H), 3.70 (m, 2H), 3.40 (m, 2H), 2.32 471(m, 4H), 1.00 (s, 9H). 6

4-(3-(1-(3,3- difluoropyrrolidine-1- carbonyl)-4oxido-1,4-azaphosphinan-4-yl)-4- fluorobenzyL)phthalazin- 1(2H)-one (CD₃OD) 8.35(d, 1H), 7.95 (d, 1H), 7.84 (m, 3H), 7.67 (m, 1H), 7.22 (m, 1H), 4.44(s, 2H), 3.66 (m, 8H), 2.40 (m, 4H), 2.10 (m, 2H), 1.19 (t, 1H). 506 7

4-(4-fluoro-3-(4-oxido-1- (tetrahydrofuran-2- carbonyl)-1,4-azaphosphinan-4- yl)benzyl)phthalazin- 1(2H)-one (DMSO-d6) 12.58 (s,1H), 8.26 (d, 1H), 8.00 (d, 1H), 7.84 (m, 3H), 7.59 (m, H), 7.28 (m,1H), 4.38 (s, 2H), 3.63 (m, 2H), 3.46 (m, 2H), 2.23 (m, 3H), 2.00 (m,3H), 1.75 (m, 5H). 471 8

4-(4-fluoro-3-(4-oxido-1- pivaloyl-1,4- azaphosphinan-4-yl)benzyl)phthalazin- 1(2H)-one (CDCl₃) 10.22 (s, 1H), 8.44 (d, 1H),7.98 (m, 1H), 7.76 (m, 3H), 7.47 (m, 1H), 7.05 (m, 1H), 4.67 (m. 2H),4.34 (s, 2H), 3.67 (m, 2H), 2.32 (m, 2H), 2.06 (m, 2H), 1.35 (s, 9H).457 9

4-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1- yl)methyl)phenyl)-N,N-dimethyl-1,4- azaphosphinane-1- carboxamide 4-oxide (CDCl₃) 10.14 (s,1H), 8.44 (d, 1H), 7.96 (m, 1H), 7.80 (m, 3H), 7.45 (m, 1H), 7.07 (m,1H), 4.34 (s, 2H), 3.96 (m, 2H), 3.65 (m, 2H), 2.89 (s, 6H), 2.42 (m,2H), 2.03 (m, 2H), 443 10

4-(4-fluoro-3-(4-oxido-1- pivaloyl-1,4- azaphosphinan-4-yl)benzyl)phthalazin- 1(2H)-one (DMSO-d₆, 300 MHz) 12.58 (s, 1H), 8.26(d, 1H), 8.00 (d, 1H), 7.84 (m, 3H), 7.59 (m, IH), 7.28 (m, 1H), 4.38(s, 2H), 3.67 (m, 2H), 3.44 (m, 2H), 3.27 (m, 4H), 2.23 (m, 469 2H),2.00 (m, 2H), 1.75 (m, 4H).

Compounds of Examples 3-10 were prepared using the appropriate startingmaterials and reagents according to the same procedures as in Example 2.

Example 11(E/Z)—N-(azetidin-1-yl(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4-oxido-1,4-azaphosphinan-1-yl)methylene)cyanamide

Synthesis of(E/Z)—N-(azetidin-1-yl(4-(2-fluoro-5-((4-oxo-3,4-dihydrophthalazin-1-yl)methyl)phenyl-4-oxido-1,4-azaphosphinan-1-yl)methylene)cyanamide(11)

Dimethyl N-cyanodithioiminocarbonate (132 mg, 0.90 mmol), DIPEA (157 μL,0.90 mmol), and 2.1 (85 mg, 0.18 mmol) were mixed together inisopropanol (2 mL) and stirred at 100° C. overnight. After cooling tor.t., azetidine hydrochloride (169 mg, 1.80 mmol) and DIPEA (157 μL,0.90 mmol) were added and the mixture was stirred at 110° C. overnight.The concentrated residue was subjected to prep-TLC using 10% MeOH/DCMand lyophilized to give 11 as a white powder (40 mg, 46.3%). ¹H NMR(DMSO-d₆, 300 MHz) δ 12.55 (s, 1H), 8.24 (d, 1H), 8.00 (d, 1H), 7.89 (m,1H), 7.78 (m, 2H), 7.61 (m, 1H), 7.28 (m, 1H), 4.38 (s, 1H), 4.24 (t,2H), 3.70 (m, 2H), 2.20 (m, 8H). LCMS (ESI+) m/z=479.0 (M+H).

Example 124-(4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one

Synthesis of4-(4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one(12)

A mixture of 2.1 (50 mg, 0.12 mmol), DIPEA (107 μL, 0.61 mmol), and2-chloropyrimidine (70 mg, 0.61 mmol) in isopropanol (1 mL) was stirredat 100° C. overnight, concentrated and prep-TLC using 10% MeOH/DCM andlyophilized to afford 3a as a white powder (30 mg, 54.4%). ¹H NMR(CD₃OD, 300 MHz) δ 8.38 (m, 3H), 7.96 (d, 1H), 7.85 (m, 3H), 7.63 (m,1H), 7.16 (m, 1H), 6.69 (t, 1H), 4.73 (m, 3H), 4.43 (s, 2H), 3.91 (m,2H), 2.37 (m, 2H), 2.05 (t, 2H). LCMS (ESI+) m/z=451.2 (M+H).

Examples 13-37

LCMS Example ¹H NMR (300 MHz) m/z No. R^(D) Chemical Name (Solvent) δppm (M + H) 13

4-(3-(1-(6-chloropyridazin- 3-yl)-4-oxido-1,4- azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin- 1(2H)-one (CDCl₃) 9.96 (s, 1H), 8.45 (d, 1H),7.96 (m, 1H), 7.78 (m, 3H), 7.46 (m, 1H), 7.33 (d, 1H), 7.00 (m, 2H),4.66 (m, 2H), 4.33 (s, 2H), 3.98 (m, 2H), 2.40 (m, 2H), 484 2.12 (m,2H). 14

6-(4-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4-oxido- 1,4-azaphosphinan-1- yl)nicotinonitrile(CDCl₃) 10.23 (s, 1H), 8.46 (m, 2H), 7.98 (m, 1H), 7.75 (m, 4H), 7.40(m, 1H), 7.01 (m, 1H), 6.75 (d, 1H), 4.67 (m, 2H), 4.34 (s. 2H), 3.95(m, 2H), 2.33 (m, 2H), 474.0 2.11 (m, 2H). 15

4-(4-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4-oxido- 1,4-azaphosphinan-1- yl)benzonitrile(DMSO-d₆) 8.38 (d, 1H), 8.08 (d, 1H),7.90 (m, 7H),7.65 (m, 1H), 7.25 (m,1H), 4.47 (s, 2H), 4.05 (m, 2H), 3.26 (m, 2H), 2.36 (m, 2H), 1.76 (m,2H). 473.0 16

2-(4-(2-fluoro-5-((4-oxo- 3,4-dihydrophthalazin-1-yl)methyl)phenyl)-4-oxido- 1,4-azaphosphinan-1- yl)nicotinonitrile(DMSO-d₆) 12.57 (s, 1H), 8.43 (m, 1H), 8.23 (d, 1H), 8.10 (dd, 1H), 7.99(d, 1H), 7.82 (m, 3H), 7.59 (m, 1H), 7.25 (m, 1H), 6.96 (t, 1H), 4.38(s, 2H), 4.21 (m, 2H), 3.85 474.0 (m, 2H), 2.34 (m, 2H), 2.16 (m, 2H).17

4-(3-(1-(2-chloropyrimidin- 4-yl)-4-oxido-1,4 azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin- 1(2H)-one 484.0 18

4-(3-(1-(4-chloropyrimidin- 2-yl)-4-oxido-1,4- azaphosphinan-4-yl)-4-fluorobenzylphthalazin- 1(2H)-one 484.0 19

4-(4-fluoro-3-(4-oxido-1- (pyridin-2-yl)-1,4- azaphosphinan-4-yl)benzyl)phthalazin-1(2H)- one 449.0 20

4-(3-(1-(3-chloro-5- (trifluoromethyl)pyridin-2- yl)-4-oxido-1,4-azaphosphinan-4-yl)-4- fluorobenzyyl)phthalazin- 1(2H)-one 551.9 21

4-(4-fluoro-3-(4-oxido-1- (quinazolin-4-yl)-1,4- azaphosphinan-4-yl)benzyl)phthalazin-1(2H)- one 500.0 22

4-(3-(1-(6-chloropyrimidin- 4-yl)-4-oxido-1,4- azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin- 1(2H)-one 484.0 23

4-(4-fluoro-3-(1-(3- fluoropyridin-2-yl)-4-oxido- 1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)- one 467.0 24

4-(4-fluoro-3-(4-oxido-1-(5- (trifluoromethyl)pyridin-2-yl)-1,4-azaphosphinan-4- yl)benzyl)phthalazin-1(2H)- one 517.0 25

4-(4-fluoro-3-(1-(6- fluoropyridin-2-yl)-4-oxido- 1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)- one 467.0 26

4-(4-fluoro-3-(4-oxido-1-(4- (trifluoromethyl)pyridin-2-yl)-1,4-azaphosphinan-4- yl)benzyl)phthalazin-1(2H)- one 517.0 27

4-(4-fluoro-3-(4-oxido-1-(3- (trifluoromethyl)pyridin-2-yl)-1,4-azaphosphinan-4- yl)benzyl)phthalazin-1(2H)- one 517.0 28

4-(4-fluoro-3-(1-(3,5- difluoropyridin-2-yl)-4-oxido-1,4-azaphosphinan-4- yl)benzyl)phthalazin-1(2H)- one 485   29

4-(4-fluoro-3-(1-(5- fluoropyridin-2-yl)-4-oxido- 1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)- one 467.0 30

4-(4-fluoro-3-(4-oxido-1- (quinazolin-2-yl)-1,4- azaphosphinan-4-yl)benzyl)phthalazin-1(2H)- one 500.0 31

4-(4-fluoro-3-(4-oxido-1-(6- (trifluoromethyl)pyridin-2-yl)-1,4-azaphosphinan-4- yl)benzyl)phthalazin-1(2H)- one 517.0 32

4-(4-fluoro-3-(4-oxido-1- (thiazol-2-yl)-1,4- azaphosphinan-4-yl)benzyl)phthalazin-1(2H)- one 455.0 33

4-(4-fluoro-3-(4-oxido-1- (thiadiazol-2-yl)-1,4- azaphosphinan-4-yl)benzyl)phthalazin-1(2H)- one 456.0 34

4-(4-fluoro-3-(4-oxido-1-(3- (acetyl)pyridin-2-yl)-1,4- azaphosphinan-4-yl)benzyl)phthalazin-1(2H)- one 491.2 35

(±)-4-(4-fluoro-3-(4-oxido- 1-(3-(1- hydoxyethyl)pyridin-2-yl)-1,4-azaphosphinan-4- yl)benzyl)phthalazin-1(2H)- one 493.1 35

4-(4-fluoro-3-(4-oxido-1-(5- (fluoro)pyrimidin-2-yl)-1,4azaphosphinan-4- yl)benzyl)phthalazin-1(2H)- one 468.1 36

4-(4-fluoro-3-(4-oxido-1-(5- (chloro)pyrimidin-2-yl)-1,4-azaphosphinan-4- yl)benzyl)phthalazin-1(2H)- one 484.1 37

4-(4-fluoro-3-(4-oxido-1-(5- (n-propyl)pyrimidin-2-yl)-1,4-azaphosphinan-4- yl)benzyl)phthalazin-1(2H)- one 492.2

Compounds of Examples 13-37 were prepared using the appropriate startingmaterials and reagents following the same procedure as in Example 12.

Example 384-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one

Synthesis of4-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one(38)

Acetic acid (56 μL, 0.98 mmol) was added to a solution of compound 2.1(100 mg, 0.25 mmol) and [(1-ethoxy-1-cyclopropyl)oxy]trimethylsilane (74μL, 0.37 mmol) in MeOH (6 mL) and stirred at r.t. for 5 min. NaBH₃CN (25mg, 0.40 mmol) was added and the mixture stirred at 60° C. for 4 h,concentrated, diluted in EtOAc (30 mL), washed with sat. NaHCO₃ (10 mL),brine (10 mL), dried over MgSO₄, concentrated and prep-TLC using 10%MeOH/DCM and lyophilized to afford 38 as a white powder (60 mg, 59.5%).¹H NMR (CDCl₃, 300 MHz) d 10.24 (s, 1H), 8.45 (d, 1H), 7.96 (m, 1H),7.76 (m, 3H), 7.43 (m, 1H), 7.05 (m, 1H), 4.33 (s, 2H), 3.17 (m, 31H),2.28 (m, 2H), 1.93 (m, 6H), 0.55 (d, 2H). LCMS (ESI+) m/z=412.2 (M+H).

Examples 39-48

Example ¹H NMR (300 MHz) LCMS No. R^(D) Chemical Name (Solvent) δ ppmm/z (M + H) 39

4-(3-(1-cyclobutyl-4- oxido-1,4-azapho sphinan- 4-yl)-4-fluorobenzyl)phthalazin- 1(2H)-one (CDCl₃) 9.85 (s, 1H), 8.45 (d. 1H),7.93 (m, 1H), 7.77 (m, 3H), 7.43 (m, 1H), 7.07 (m, 1H), 4.33 (s, 2H),3.01 (m, 3H), 2.72 426.2 (m, 2H), 2.34 (m, 2H), 1.96 (m. 6H), 1.72 (m,2H). 40 Me 4-(4-fluoro-3-(1-methyl-4- 386.0 oxido-1,4-azaphosphinan-4-yl)benzyl)phthalazin- 1(2H )-one 41 Et 4-(3-(1-ethyl-4-oxido-1,4-400.1 azaphosphinan-4-yl)-4- fluorobenzyl)phthalazin- 1(2H)-one 42 CHMe₂4-(4-fluoro-3-(1- 414.2 isopropyl-4-oxido-1,4- azaphosphinan-4-yl)benzyl)phthalazin- 1(2H)-one 43

4-(3-(1- (cyclopropylmethyl)-4- oxido-1,4-azaphosphinan- 4-yl)-4- 426.2fluorobenzyl)phthalazin- 1(2H)-one 44 CH₂CHMe₂ 4-(4-fluoro-3(1-isobutyl-427.2 4-oxido-1,4- azaphosphinan-4- yl)benzyl)phthalazin- 1(2H)-one 45n-Pr 4-(4-fluoro-3-(4-oxido- 414.2 45propyl-1,4- azaphosphinan-4-yl)benzyl)phthalazin- 1(2H)-one 46 CH₂Bu^(t) 4-(4-fluoro-3-(1-neopentyl-4-oxido-1,4- azaphosphinan-4- yl)benzyl)phthalazin- 1(2H)-one 47CH₂CHEt₂ 4-(4-fluoro-3-(1-neopentyl- 4-oxido-1,4- azaphosphinan-4-yl)benzyl)phthalazin- 1(2H)-one 48 (CH₂)₂CHMe₂ 4-(4-fluoro-3-(1-isopentyl)-4-oxido-1,4- azaphosphinan-4- yl)benzyl)phthalazin- 1(2H)-one

Compounds of Examples 39-48 were prepared using the appropriate startingmaterials and reagents following the same procedures as in Example 38.

Example 494-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)phthalazin-1(2H)-one

Synthesis of4-(4-fluoro-3-(4-oxido-1-(2,2,2-trifluoroethyl)-1,4-azaphosphinan-4-yl)benzyl)phthalazin-1(2H)-one(49)

2,2,2-trifluoroethanol (360 μL, 5.00 mmol) was added to a solution oftrifluoromethanesulfonic anhydride (839 μL, 5.00 mmol) in toluene (3 mL)at 0° C. and stirred for 1 h at rt. 1.2 (50 mg, 0.12 mmol) and DIPEA(107 μL, 0.61 mmol) were added and the mixture was stirred at 100° C.overnight, concentrated and prep-TLC using 10% MeOH/DCM and lyophilizedto afford 49 as a light brown powder. ¹H NMR (CD₃OD, 300 MHz) δ 8.35 (d,1H), 7.94 (d, 1H), 7.84 (m, 3H), 7.66 (m, 1H), 7.22 (m, 1H), 4.43 (s,2H), 3.24 (s, 2H), 2.42 (m, 4H), 2.01 (m, 4H). MS (ESI+) m/z=454.2(M+H).

Example 504-[[4-fluoro-3-(4-methyl-4-oxo-1,4-azaphosphinane-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one

Step 50.1: Synthesis of3-(3-cyano-4-fluorobenzylidene)isobenzofuran-1(3H)-one (50.1)

To a mixture of 1.3 (2.42 g, 10.0 mmol) and2-fluoro-5-formylbenzonitrile (1.49 g, 10 mmol) in THF (20 mL) was addedtriethylamine (1.11 g, 11 mmol) dropwise over 5 min, and the temperaturewas maintained below 15° C. The reaction mixture was slowly warmed to20° C. over 1 h and was then concentrated in vacuo. The residue wastriturated with water (20 mL). The solid was collected by filtration,washed with water (5 mL), ether (10 mL), and hexane (10 mL), and wasdried to produce compound 50.1 as a mixture of E and Z isomers. Thematerial was used without further purification.

Step 50.2: Synthesis of2-Fluoro-5-[(4-oxo-3H-phthalazin-1-yl)methyl]benzoic Acid (5.2)

As such, to a stirred suspension of 50.1 (˜10 mmol) in water (20 mL) wasadded aqueous NaOH (10 N, 5 mL). The reaction was subsequently heated to100° C. for 1 h. After the reaction mixture was cooled to roughly 70° C.and hydrazine hydrate (5.0 mL, 100 mmol) was added. The mixture wasstirred at 70° C. for 24 h. The reaction was cooled mom temperature andacidified with HCl (8 N, ca. 80 mL) to pH 4. After reaction was againcooled to room temperature, the solid was collected with filtration,washed with water (10 mL), ether (3×10 mL) and was dried to producecompound 50.2 (2.41 g) as a white solid. MS (ESI+) m/z=299 (M+H).

Step 50.3: Synthesis of4-[[4-fluoro-3-(4-methyl-4-oxo-1,4-azaphosphinane-1-carbonyl)phenyl]methyl]-2H-phthalazin-1-one(50)

HATU (85 mg, 0.22 mmol) was added to a solution of compound 40.2 (59 mg,0.20 mmol) and DIPEA (144 μL, 0.83 mmol) in DMF (3 mL). After 5 min.4-methyl-1,4-azaphosphinane 4-oxide (preparation seen WO2011/002523A1)39 mg, 0.30 mmol) was added and stirred at r.t. overnight, concentrated,diluted in EtOAc (30 mL), washed with H₂O (2×30 mL), brine (30 mL),dried over MgSO4, concentrated and prep-TLC using 15% MeOH/DCM, followedby lyophilization gave 50 as an off white powder. MS (ESI+) m/z=414(M+H).

Examples 51-53

Example LCMS No. “R group” Chemical Name m/z (M + H) 51

4-[[4-fluoro-3-(4-ethyl-4-oxo-1,4-azaphosphinane-1-carbonyl)phenyl]methyl]- 2H-phthalazin-1-one 429 52

4-[[4-fluoro-3-(4-isopropyl-4-oxo-1,4-azaphosphinane-1-carbonyl)phenyl]methyl]- 2H-phthalazin-1-one 443 53

4-[[4-fluoro-3-(4-ethoxyl-4-oxo-1,4-azaphosphinane-1-carbonyl)phenyl]methyl]- 2H-phthalazin-1-one 445

Compounds of Examples 51-53 were prepared using the appropriate startingmaterials and reagents according to the same procedures as in Example50. The 1,4-azaphosphinane 4-oxide derivatives were made by using thesame procedures as described in WO2011/002523A1.

Example 544-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)-7-fluorophthalazin-1(2H)-one

Step 1, methyl 2-(2-(3-bromo-4-fluorophenyl)ethynyl)-5-fluorobenzoate(54.1): To a flask with 2-bromo-4-ethynyl-1-fluorobenzene (1.3 g, 6.5mmole) and methyl 5-fluoro-2-iodobenzoate (2 g, 7.1 mmole) in DMF (10mL) was added triethyl amine (2 mL), CuI (200 mg), Pd(dppf)Cl2 (100 mg)under nitrogen, the mixture was heated to 80° C. overnight. Aftercooling down, the solvent was removed and the residue was purifiedthrough chromatography to provide the desired product (1.67 g).

Step 2, 4-(3-bromo-4-fluorobenzyl)-7-fluorophthalazin-1(2H)-one (54.2):A mixture of methyl2-(2-(3-bromo-4-fluorophenyl)ethynyl)-5-fluorobenzoate (54.1, 1.5 g, 4.3mmole) and 9 mmole of 80% NH2NH2.H2O were refluxed in 10 mL of ethanolfor 8 h until full disappearance of the ester. The reaction mixture wascooled and the precipitate was filtered. A mixture of the hydrazide and1.2 equiv. of KOH was refluxed in 10 ml of EtOH until full disappearanceof the hydrazide. The desired product was purified throughchromatography to give the desired product (860 mg).

Step 3, compound (54.3): Palladium (II) acetate (386 mg, 1.72 mmol) and1,3-bis(diphenylphosphino)-propane (710 mg, 1.72 mmol) were stirred inDMF (30 mL) for 15 min. A solution of phosphine oxide (3.82 g, 11.47mmol), 54.2 (2.40 g, 11.47 mmol), and DIPEA (10 mL, 57.36 mmol) in DMF(10 mL) was added and the reaction mixture stirred at 120° C. overnight.After concentrating, column chromatography using 0-10% (gradient)MeOH/DCM gave a light yellow semisolid, which was diluted in DCM (100mL), washed with H₂O (2×100 mL), the aqueous layer was extracted withDCM (100 mL), combined organic layer was then washed with brine (100mL), dried over MgSO₄, concentrated, sonicated in ether and filtered toafford 54.3 as a pale yellow solid (3.27 g, 61.8%).

Step 4 Compound (54.4): A mixture of 54.3 (1.00 g, 2.17 mmol), 4M HCl in1,4-dioxane (2 mL), and Pd(OH)₂/C (20% wt, wet, 1 g) in MeOH (30 mL) washydrogenated under 60 psi H_(2(g)) overnight. The reaction mixture wasfiltered through celite, cake washed with warm MeOH (100 mL), combinedfiltrates concentrated and lyophilized to give 54.4 as a pale yellowhydrochloride salt (800 mg, 90.5%).

Step 5, synthesis of4-(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorobenzyl)-7-Fluorophthalazin-1(2H)-one(54): Acetic acid (56 μL, 0.98 mmol) was added to a solution of 54.4(100 mg, 0.25 mmol) and [(1-ethoxy-1-cyclopropyl)oxy]trimethylsilane (74μL, 0.37 mmol) in MeOH (6 mL) and stirred at rt for 5 min. NaBH₃CN (25mg, 0.40 mmol) was added and the mixture stirred at 60° C. for 4 h,concentrated, diluted in EtOAc (30 mL), washed with sat. NaHCO₃ (10 mL),brine (10 mL), dried over MgSO₄, concentrated and prep-TLC using 10%MeOH/DCM and lyophilized to afford 54 as a white powder (60 mg, 59.5%).¹H NMR (CDCl₃, 300 MHz) δ 8.31 (d, 1H), 7.86 (m, 3H), 7.66 (m, 1H), 7.28(m, 1H), 3.14 (m, 4H), 2.39 (m, 2H), 2.10 (m, 2H), 1.89 (m, 1H), 0.47(m, 4H). LCMS (ESI+) m/z=430.0 (M+H).

Example 554-[(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluorophenyl)dideuteromethyl]-7-fluorophthalazin-1(2H)-one

To a solution of compound 54 (20 mg) in D₂O:D-DMSO (2 mL, 1:1) was addedDBU (1 mL) and the mixture was heated to 50° C. for 2 h. The reactionmixture was cooled down to room temperature and water was added. Thedesired product was extracted with methylene chloride and dried to givethe desired product 52 (18 mg). LCMS (ESI+) m/z=432.0 (M+H).

Example 564-(4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)benzyl)-7-fluorophthalazin-1(2H)-one

A mixture of 54.4 (50 mg, 0.12 mmol). DIPEA (107 μL, 0.61 mmol), and2-chloropyrimidine (70 mg, 0.61 mmol) in isopropanol (1 mL) was stirredat 100° C. overnight, concentrated and prep-TLC using 10% MeOH/DCM andlyophilized to afford 56 as a white powder (30 mg, 54.4%). ¹H NMR(CD₃OD, 300 MHz) δ 8.38 (m, 3H), 7.96 (d, 1H), 7.85 (m, 3H), 7.63 (m,1H), 7.16 (m, 1H), 6.69 (t, 1H), 4.73 (m, 3H), 4.43 (s, 2H), 3.91 (m,2H), 2.37 (m, 2H), 2.05 (t, 2H). LCMS (ESI+) m/z=451.2 (M+H).

Example 574-[(4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)phenyl)dideuteromethyl]-7-fluorophthalazin-1(2H)-one

The general procedure described in example 55 is followed and thedesired produce 57 is obtained.

Example 58(±)-4-[(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluoro-1-phenyl)(hydroxymethyl)]phthalazin-1(2H)-one

Step 1, synthesis of compound 58.1. To a solution of compound 1.4 (1.69g, 5.0 mmol) in DCM (20 ml) was added mCPBA (2.88 g, ˜60% pure, ˜10mmol). Reaction was stirred at room temperature for 12 hour. Thereaction was then diluted with EtOAc (80 mL), and the mixture was washedwith 20 mL each of 1 M aqueous sodium carbonate, water and brine, driedover anhydrous magnesium sulfate, filtered and concentrated to give thecrude product of 58.1, which was used without further purification

Step 2, 3 and 4, synthesis of(±)-4-[(3-(4-oxido-1,4-azaphosphinan-4-yl)-4-fluoro-1-phenyl)(hydroxymethyl)]-phthalazin-1(2H)-one(58.4). The title compound was synthesized with the same procedures asthe synthesis of compound 2.1 from compound 1.4, by using compound 58.1instead of compound 1.4. MS (ESI) m/z=388 (M+H⁺).

Step 5, synthesis of(±)-4-[(3-(1-cyclopropyl-4-oxido-1,4-azaphosphinan-4-yl)-4-fluoro-1-phenyl)(hydroxymethyl)]-phthalazin-1(2H)-one(58). The title compound was synthesized with the same procedures as thesynthesis of example 38, by using compound 58.4 instead of compound 2.1.LCMS (ESI) m/z=428 (M+H⁺).

Example 59(±)-4-{[4-fluoro-3-(4-oxido-1-(pyrimidin-2-yl)-1,4-azaphosphinan-4-yl)phenyl)](hydroxymethyl)]-7-fluorophthalazin-1(2H)-one

The title compound was synthesized with the same procedures as thesynthesis of example 12, by using compound 58.4 instead of compound 2.1.MS (ESI) m/z=466 (M+H).

Example 60 PARP-1 Enzyme Assay

Inhibition of PARP-1 enzymatic activities was measured using an HTUniversal Colorimetric PARP Assay Kit (Trevigen, catalogue #4677-096-K)following the standard procedures.

Serial dilutions of PARP compounds were added to appropriate wells. Thecompound was incubated with PARP enzyme at RT for 10 min, and thereaction was initiated by addition of the PARP substrate cocktail. Eachconcentration of compound was tested in triplicate wells. After 15 minreaction, the reaction was stopped, and the Strep-HRP was added intoeach well and incubated for 1 h at RT. After addition of TACS-Sapphire™colorimetric substrate and incubated in dark for 15 min, the OD450 wasread out with an EnVision instrument. IC₅₀ values (the concentration atwhich 50% of the enzyme activity is inhibited) were calculated, whichare determined over a range of different concentrations, normally from10 μM to 0.1 nM.

Selected compounds of the present invention were tested and theactivities (IC₅₀) are summarized in Table 2.

Example 61 PARP Cell Assay

Inhibition of intracellular PARP enzyme was determined using animmunohistochemistry (IHC) assay. The cellular assay measures theformation of poly (ADP)-ribose catalyzed by PARP inside cells. Activityindicates that the compound can permeate into the intact cells toinhibit PARP enzymes.

Materials: Anti-PAR (Ab-1) Mouse mAb (10H) (Calbiochem, AM-80);Anti-Mouse IgG (whole molecule)-FITC antibody produced in goat (sigma.F2012); DAPI (sigma. D9542).

Assay procedures: The C41 cells (Human cervical carcinoma; ATCC No.CRL-1594) were planted into 96-well plates at 8.0E4 cells/well andincubated at 37° C. overnight. Cells were washed with 37° C. warmed PBSonce and treated with test compounds for 2 h in 96-well plates. Cellswere washed with 37° C. warmed PBS once, and PARP was activated bydamaging DNA with 1.0 mM H₂O₂ for 10 min. Cells were washed withice-cold PBS once and fixed with pre-chilled methanol/acetone (7:3) at−20° C. for 10 min. After air-drying, plates were rehydrated with PBSand blocked using 5% nonfat dry milk in PBS-Tween (0.05%) (blocksolution) for 30 min at mom temperature. Cells were incubated withanti-PAR antibody 10H (1:100) in blocking solution at room temperaturefor 60 min, followed by washing with PBS-Tween20 5 times and incubationwith goat anti-mouse FIC-coupled antibody (1:50) and 1 μg/mL DAPI inblocking solution at room temperature for 60 min. After washing withPBS-Tween20 5 times, analysis was performed using Vector 3 MicroplateReader (PerkinElmer) set at the excitation (485 nm) and emission (535nm) wavelength for FITC or the excitation (364 nm) and emission (454 nm)wavelength for DAPI. PARP activity (FITC signal) was normalized withcell numbers (DAPI). The EC₅₀ values (the concentration at which 50% ofthe PARP activity is inhibited) were calculated based on the PARPactivities determined over a range of different concentrations.

Selected compounds of the present invention were tested and theactivities (EC₅₀) are summarized in Table 2.

TABLE 2 PARP Inhibition Data IC₅₀ EC₅₀ Example No. (PARP-1inhibition)^(a) (PARP cell assay)^(a) 1 +++ ND 2 + ND 3 +++ ND 4 +++ ND5 +++ ND 6 +++ ND 7 ++ ND 8 +++ ND 9 ++ ND 10 ++ ND 11 +++ ND 12 +++ +++13 +++ ++ 14 +++ +++ 15 + ND 16 +++ ND 17 +++ ND 18 +++ ++ 19 +++ ++ 20++ ND 21 +++ ++ 22 +++ +++ 23 +++ +++ 24 +++ ND 25 +++ +++ 26 +++ ND 27++ ND 28 +++ ++ 29 ND ND 30 +++ ND 31 ++ ND 32 ND ND 33 ND ND 34 +++ ND35 ++ ND 35 +++ +++ 36 +++ ++ 37 ++ ND 38 +++ +++ 39 +++ +++ 40 ++ ND 41+++ ++ 42 +++ ND 43 +++ ++ 44 +++ +++ 45 +++ +++ 46 +++ ND 47 ++ ND 48+++ ++ 49 +++ ND 50 +++ ND 51 +++ ND 52 +++ ND 53 +++ ND 54 +++ ND 55+++ ND 56 +++ ND 57 +++ ND 58 +++ ND 59 +++ ND ^(a)“+++” indicates IC₅₀or EC₅₀ value below 100 nM; “++” indicates IC₅₀ or EC₅₀ value between100 nM and 1000 nM; “+” indicates IC₅₀ or EC₅₀ value between 1000 nM and10,000 nM; and “ND” means not determined.

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

1-117. (canceled)
 118. A method for the treatment or prevention of acondition which can be ameliorated by inhibition of PARP in anindividual in need thereof, the method comprising administering to theindividual an effective amount of a compound of formula (I):

wherein R^(A) and R^(B) are taken together with the carbon atoms towhich they are attached to form a substituted or unsubstituted6-membered aromatic ring, wherein the substituted 6-membered aromaticring is substituted by R^(F), wherein R^(F) is hydrogen, halo, —CF₃,unsubstituted C₁-C₃ alkyl or unsubstituted C₁-C₃ alkoxy; each R¹ and R²is independently hydrogen, halo, hydroxy, unsubstituted C₁-C₃ alkyl orunsubstituted C₁-C₃ alkoxy; Z is a 6-membered aryl substituted withR^(C) and R^(P); R^(C) is hydrogen, halo, —CF₃, unsubstituted C₁-C₃alkyl or unsubstituted C₁-C₃ alkoxy; R^(P) is a moiety of the formula(Ia) or (Ib);

each X is independently O, S or absent; R^(D) is hydrogen, substitutedor unsubstituted alkyl, unsubstituted cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —C(O)R⁴,—C(═N—CN)NR⁸R⁹ or —C(O)NR⁵R⁶; R⁴ is an unsubstituted alkyl,unsubstituted cycloalkyl, unsubstituted alkoxy, or substituted orunsubstituted heterocyclyl; each R⁵ and R⁶ is independently hydrogen,unsubstituted alkyl or unsubstituted cycloalkyl; each R⁸ and R⁹ isindependently hydrogen, unsubstituted alkyl or unsubstituted cycloalkyl,or R⁸ and R⁹ are taken together with the nitrogen to which they areattached to form an unsubstituted heterocyclyl; R^(E) is unsubstitutedalkyl, unsubstituted cycloalkyl, unsubstituted aryl, or —OR⁷; and R⁷ isan unsubstituted alkyl or unsubstituted cycloalkyl; wherein thesubstituted alkyl, the substituted aryl, the substituted heteroaryl, andthe substituted heterocyclyl are independently substituted by one, two,three, or more substituents, wherein the substituents are independentlycyano, halo, haloalkyl, alkyl, alkylcarbonyl, cycloalkyl, or aryl;wherein said alkyl substituents are optionally substituted withhydroxyl, or a pharmaceutically acceptable salt or solvate thereof. 119.The method of claim 118, wherein the condition which can be amelioratedby inhibition of PARP is a condition selected from the group consistingof cancer, inflammatory diseases, and ischemic conditions.
 120. A methodfor the treatment of cancer comprising administering to the individualan effective amount of a compound of formula (I):

wherein R^(A) and R^(B) are taken together with the carbon atoms towhich they are attached to form a substituted or unsubstituted6-membered aromatic ring, wherein the substituted 6-membered aromaticring is substituted by R^(F), wherein R^(F) is hydrogen, halo, —CF₃,unsubstituted C₁-C₃ alkyl or unsubstituted C₁-C₃ alkoxy; each R¹ and R²is independently hydrogen, halo, hydroxy, unsubstituted C₁-C₃ alkyl orunsubstituted C₁-C₃ alkoxy; Z is a 6-membered aryl substituted withR^(C) and R^(P); R^(C) is hydrogen, halo, —CF₃, unsubstituted C₁-C₃alkyl or unsubstituted C₁-C₃ alkoxy; R^(P) is a moiety of the formula(Ia) or (Ib):

each X is independently O, S or absent; R^(D) is hydrogen, substitutedor unsubstituted alkyl, unsubstituted cycloalkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, —C(O)R⁴,—C(═N—CN)NR⁸R⁹ or —C(O)NR⁵R⁶; R⁴ is an unsubstituted alkyl,unsubstituted cycloalkyl, unsubstituted alkoxy, or substituted orunsubstituted heterocyclyl; each R⁵ and R⁶ is independently hydrogen,unsubstituted alkyl or unsubstituted cycloalkyl; each R⁸ and R⁹ isindependently hydrogen, unsubstituted alkyl or unsubstituted cycloalkyl,or R⁸ and R⁹ are taken together with the nitrogen to which they areattached to form an unsubstituted heterocyclyl; R^(E) is unsubstitutedalkyl, unsubstituted cycloalkyl, unsubstituted aryl, or —OR⁷; and R⁷ isan unsubstituted alkyl or unsubstituted cycloalkyl; wherein thesubstituted alkyl, the substituted aryl, the substituted heteroaryl, andthe substituted heterocyclyl are independently substituted by one, two,three, or more substituents, wherein the substituents are independentlycyano, halo, haloalkyl, alkyl, alkylcarbonyl, cycloalkyl, or aryl;wherein said alkyl substituents are optionally substituted withhydroxyl, or a pharmaceutically acceptable salt or solvate thereof. 121.The method of claim 120, wherein the cancer is a breast cancer, anovarian cancer or a brain cancer.
 122. The method of claim 120, whereinthe cancer is a cancer which is deficient in HR dependent DNA DSB repairactivity.
 123. The method of claim 120, wherein the cancer is a BRCA-1or BRCA-2 deficient tumor.
 124. The method of claim 120, wherein thecancer is a PTEN mutated tumor. 125-132. (canceled)